JPH049373A - Benzimidazole derivative - Google Patents

Abstract

NEW MATERIAL:Compounds of formula I (R<1> is alkyl; R<2> and R<3> are group capable of forming anion or capable of changing thereinto; Ring A is benzene ring which may have other substituents than R<2> group; X is bond linking phenylene with phenyl directly or through spacer of atomic chain having length of <=2) or its salts. EXAMPLE:2-Butyl-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimid azole-7- carboxylic acid. USE:Having a strong angiotensin II antagonism and antihypertensive action. A remedy for circulatory diseases such as hypertension, heart disease, cerebral apoplexy, kidney disease accompanied by proteinuria and arteriosclerosis. PREPARATION:A compound of formula II is reacted with an alkylation agent of formula III (W is halogen) in the presence of a base (e.g. NaH) in a solvent such as DMF at a temperature under ice cooling-room temperature to obtain the objective compound of formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention relates to novel benzimidazole derivatives having excellent pharmacological effects and synthetic intermediates thereof.

More specifically, the present invention provides strong angiothenes [wherein
R1 represents an alkyl group which may be substituted, R2 and R3 each represent a group capable of forming an anion or a group convertible thereto, and the ring has a substituent other than the group represented by formula R2. Indicates a benzene ring that may be
X indicates that a phenylene group and a phenyl group are bonded directly or via a spacer having two or less atomic chains, and salts thereof.

[Prior Art and Problems to be Solved by the Invention] The renin-angiotensin system, together with the aldosterone system, is involved in homeostasis regulating functions such as systemic blood pressure, body fluid volume, and electrolyte balance. Regarding the relationship between the renin-angiotensin system and hypertension, angiotensin I [(A
With the development of inhibitors of I[) converting enzyme (ACE inhibitors), it has become a clear priority. Since angiotensin 2 constricts blood vessels and increases blood pressure via angiotensin 2 receptors on cell membranes, its antagonist can be used in the treatment of hypertension caused by angiotensin, similar to ACE inhibitors. Until now, a large number of angiotensif m analogues such as saralasin, [Sar', Al2a'l A II
etc. have strong angiotensin antagonistic effects.
It has been reported that However, it has been reported that peptide antagonists have a short action time when administered parenterally and are ineffective when administered orally [M, A.

0ndetti and D. W. Cushman.
, Annual Reports in Medici
nal Chemistry, 13.8282-91
(197).

On the other hand, in order to solve the problems of these peptide angiotensin antagonists, research has been conducted on non-peptide angiotensin antagonists. That is, an imidazole derivative having an angiotensin antagonistic action, which was the first step in this direction, was published in JP-A-56-71073.56-
No. 71074.57-92270.58-157768, USP4°355.040 and USP4,34
0.598 etc. After that, EP-025
3310, EP-0291969, EP-032437
7゜JP 63-23868 and JP 1-1
No. 17876 discloses improved imidazole derivatives, and EP-0323841 and JP-A-1-2870 disclose improved imidazole derivatives.
Publication No. 71 discloses pyrrole, pyrazole and triazole derivatives as angiotensin II antagonists.

The present inventors have long believed that in order for a compound to be a clinically useful drug for treating cardiovascular diseases such as hypertension, heart disease, and stroke, it must have angiotensin receptor antagonistic activity and be potent when administered orally. We have conducted intensive research based on the idea that it is necessary to have a strong angiotensin antagonistic effect and antihypertensive effect.

Furthermore, USP 4,880,804--benzimidazole derivative 1 has angiotensin receptor antagonistic activity and is active in renally hypertensive rats by intravenous administration.
For example, a compound (A) [a compound represented by the following formula (A)] having a hydroxymethyl, methoxy, formyl, chloro or carboxy group at the 5- and/or 6-position is exemplified. However, most of the compound IkJ (A) is inactive orally, and only the 6-hydroxymethyl form and 6-chlor form are orally administered (lOO
mg/kg or less). However, compounds with such strength are not sufficiently satisfactory for practical use as pharmaceuticals.

[Means for Solving the Problems] The present inventors have discovered that a specific compound not specifically described in US Pat. A strong AI [
They discovered that it has antagonistic and antihypertensive effects, and after further research, they completed the present invention.

That is, the present invention is based on the formula: Furthermore, in the US patent, the compounds specifically described, including the above compound (A), are those having substituents at the 5 and/or 6 positions on the benzene ring of benzimidazole. There is no mention of benzimidazole derivatives having a substituent at the 4- or 7-position.

[In the formula, R1 represents an alkyl group that may be substituted, R2 and R3 each represent a group that can form an anion or a group that can be converted into an anion, and ring A has a substituent other than the group represented by formula R2. X represents a benzene ring which may have a benzene ring, and X is a compound represented by 1 or a salt thereof, which indicates that a phenylene group and a phenyl group are bonded directly or via a spacer having two or less atomic chains.

Regarding the general formula (1), the alkyl group as R1 is a lower alkyl group having about 1 to 8 carbon atoms, and may be either linear or dibranched, such as methyl, ethyl, propyl, isopropyl, butyl, and isobutyl.

5ee-7'tyl, t-butyl, pentyl, l-pentyl.

Examples include hexyl, hegetyl, octyl, etc., and the alkyl group is a hydroxyl group, an optionally substituted amino group, halogen, lower (c 1-4) alkylthio, lower (C 1-
4) May be substituted with an alkoxy group or the like. R1 is a hydroxyl group, an amino group, a nitrogen group, or a lower (C
t-a) Lower (C
2-8) Alkyl group is preferred.

Examples of the group capable of forming an anion as R2 or the group capable of converting thereto include the formula -(CH*)nCOD [wherein D is hydrogen, a hydroxyl group, an optionally substituted amino group,]\roken, substituted an alkoxy group (e.g., an alkyl moiety is a hydroxyl group,
Optionally substituted amino group, /10 hydrogen, carbon number 1
-6 linear or branched lower alkyl groups (e.g. methyl, ethyl, n-propyl.

Isopropyl, n-butyl, isobutyl, t-butyl,
n-pentyl, inpentyl, 2-opentyl, etc.) or a cycloalkyl group having 5-7 carbon atoms (e.g., cyclopentyl, cyclohexyl, cycloheptyl, etc.)
R/ / / / is a linear or branched lower alkyl group having 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 5ec-butyl, t-butyl, n-pentyl) , impentyl, neopentyl, etc.), cycloalkyl groups having 5-7 carbon atoms (e.g.,
cyclopentyl, cyclohexyl, cycloheptyl, etc.), a cycloalkyl group having 5 to 7 carbon atoms (e.g., cyclopentyl, cyclohexyl, cycloheptylnato), or a lower alkyl group having 1 to 3 carbon atoms substituted with a phenyl group (e.g., Methyl, ethyl.

n-propyl, isopropyl, etc.) or carbon number 2-
3 lower alkenyl group (eg, vinyl, propenyl, allyl, impropenyl, etc.), an optionally substituted phenyl group (eg, phenyl, etc.).

Straight chain or branched lower alkoke group having i6 carbon atoms (
Examples: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, 5ec-butoxy, t-butoxy, n-pentyloxy, isopentyloxy, neopentyloxy, etc.), cycloalkyloxy groups with 5-7 carbon atoms ( e.g., cyclopentyloxy, cyclohexyloxy, cyclohebutyloxy, etc.), cycloalkyl groups having 5-7 carbon atoms (e.g., cyclopentyl, cyclohexyl,
cyclohebutyl, etc.) or a lower alkoxy group having i3 carbon atoms substituted with a phenyl group (e.g., methoxy, ethoxy, n-propoxy, impropoxy, etc.), an optionally substituted phenoxy group (e.g., phenoxy, etc.), or an optionally substituted benzyloxy group (e.g., benzyloxy, etc.), lower (Ct
-S) Lower (C, -a) alkokyne optionally substituted with alkylthio or optionally substituted dioxolenyl (e.g., 5-methyl-2-oxo-1,3=dioxolen-4-yl, etc.) groups, preferably the alkyl moiety is a hydroxyl group, an optionally substituted amino group, a halogen, a lower (Cz-s) alkanoyloxy, a 1-lower (Ct-a) alkoxy group.

lower (Ct-S) alkylthio, lower (Cl-1) alkoxy group which may be substituted with a lower (Ct-i) alkoxycarbonyloxy group, etc.), and n is 1 indicating 0.1. cyano, optionally protected tetrazolyl, phosphoric acid, sulfonic acid, phenolic hydroxyl group, optionally substituted alkoxy group, trifluoromethanesulfonic acid amide, and Lower (c 1
-3) Alkyl groups, etc., which can form anions or can be converted into anions by undergoing metabolism under biological or physiological conditions or chemically (e.g., by oxidation, reduction, hydrolysis, etc.) Compounds in which R2 is a group capable of chemically forming an anion or a group convertible thereto are also useful as synthetic intermediates.

As R2, in the formula -(CH2)nCOD I, D
is hydrogen, hydroxyl group, amino, N-lower (CI-a) alkylamino, N, N-di-lower (CI-a) alkylamino, or the alkyl moiety is hydroxyl group, amino, or halogen.

lower<cz-*)alkanoyloxy, 1-lower (C1
-, ) alkoxy, lower (CI-6) alkylthio or lower (CI-6) alkoxycarbonyloxy -
represents lower (C+-a) alkoxy which may be substituted with (Cz-s) alkanoyl, benzoyl, etc.) group optionally protected with tetrazolyl is preferred, and furthermore, in the formula -〇〇-D'E, D' is a hydroxyl group,
Amino, N-lower (CI-a) alkylamino, N, N
- di-lower (C1-4) alkylamino or alkyl moiety is a hydroxyl group, amino, halogen, lower (CZ-S) alkanoyloxy, 1-lower (CI-S) alkoxy, lower (CI-S) alkylthio or lower (CI-S) -S)
A group represented by [representing lower (CI-s)alkoxy which may be substituted with alkoxycarbonyloxy or the like], or tetrazolyl which may be protected with an alkyl or acyl group is preferred.

An example of a group capable of forming an anion or a group convertible thereto as R3 is carboxyl.

Tetrazolyl, trifluoromethanesulfonic acid amide (
-NHS O2CF s), phosphoric acid, sulfonic acid, cyano, lower (CI-4) alkoxycarbonyl, etc., and these groups are protected with an optionally substituted lower alkyl group or acyl group, etc. Any group that can form an anion or a group that can be converted into an anion under biological or physiological conditions or chemically may be used.

In addition, compounds in which RX is a group that can chemically form an anion (for example, by oxidation, reduction, or hydrolysis) or a group that can be converted into an anion (for example, cyano),
Useful as a synthetic intermediate.

R1 is preferably carboxyl or tetrazolyl.

Examples of substituents other than the group represented by R2 on the benzene ring A include halogen (e.g., F, (1°B), etc.),
Nitro-, cyano-, it-substituted amino group c examples, amino, N-lower (C1-4) alkylamino (e.g.
methylamino, etc.), N,N-di-lower (CI-a) alkylamino (eg, dimethylamino, etc.), N-arylamino (eg, phenylamino, etc.).

Alicyclic amines (e.g., morpholino, piperidino, piperazino, N-phenylpiperazino, etc.), etc.]] Formula 1 -Y-
In the R formula, Y represents a bond, -O-, -S-, or -C-, and R is hydrogen or an optionally substituted lower alkyl group (e.g., a hydroxyl group, an optionally substituted amino group) , halogen, lower (C1-4) alkyl which may be substituted with a lower (C1-4) alkoxy group, etc.), or a group represented by 1 of the formula -Go-D
"[In the formula, D" is hydrogen, an optionally substituted alkoxy group [eg, the alkyl moiety is a hydroxyl group].

An optionally substituted amino group, halogen, lower (C1
-4) Lower optionally substituted with an alkoxy group, etc.
(CI-4) Alkoxy, etc., optionally substituted amino groups [e.g., amino, N-lower (CI-4) alkylamino (e.g., methylamino, etc.), N, N-di-lower (
C+-,)alkylamino (e.g. dimethylamino, etc.)
, N-arylamino (e.g., phenylamino, etc.), alicyclic amino (e.g., morpholino, piperidino, piperazino, N-phenylpiperazino, etc.)], halogen (e.g., chlor, etc.) or 1 representing a hydroxyl group Among them, halogen, lower (CI-4) alkyl, lower (Cl-4) alkoxy, nitro, and groups represented by the formula -
〇〇-D"' [wherein, D"' is a hydroxyl group or a lower (CI
-Z) represents alkoxy] or lower (
Amino which may be substituted with C□-4) alkyl is preferred, and halogen and lower (CI-4) alkyl are more preferred.

X indicates that adjacent phenylene groups and phenyl groups are bonded directly or via a spacer of 2 or less atomic chains, and atoms II! The 12 or less spacer may be any divalent chain whose straight chain portion has 1 or 2 atoms, and may have a side chain. Specifically, examples include lower grades (clj: 'al).

Among the compounds represented by the above formula (1), compounds represented by the formula [wherein R' is a hydroxyl group, an amino group, /10 or t: is a lower (
CI-4) Lower (optionally substituted with an alkoxy group)
Cx-s) alkyl; R2 represents the formula -Co-D' [wherein D' is a hydroxyl group, amino, N-lower (CI-4) alkylamino, N,N-di-lower (CI-4) alkylamino or a group represented by 1 representing lower (CI-t) alkoxy whose alkyl moiety may be substituted with a hydroxyl group, amino halogen or lower (CI-4) alfkyne, or tetrazolyl which may be protected with an alkyl or acyl group. R3 represents a carboxyl or tetrazolyl group which may be protected with an alkyl or acyl group, and R' represents hydrogen, halogen, lower (C, -
4) Alkyl, lower (C1-4) alkoxy, nitro,
Formula -CO-D"' [wherein D"' is a hydroxyl group or a lower (
C□-1) alkoxy] or amino optionally substituted with lower (C1-4) alkyl (preferably hydrogen, lower (CI-4) alkyl, halogen, more preferably hydrogen) ] Compound (I') represented by is preferred.

The compound of general formula (1) above can be produced, for example, by the method shown below.

Reaction (a) Reaction (d) [In the formula, R', R2, R3, A and X have the same meanings as above.

W represents a halogen atom. 1 [In the formula, each symbol has the same meaning as above. ] Reaction (e) [In the formula, each symbol has the same meaning as above. ] Reaction (c) [wherein R', R2, R3, A and X have the same meanings as above.

Y represents iminoether, iminothioether, carboxyl, amidine, cyano group, etc. Co-reaction (f) [wherein R', R", A and X have the same meanings as above. R'
represents optionally substituted lower (CI-a) alkyl. ] In formula 1, R', R3, R', A and X have the same meanings as above.

n represents 0 or l. ] Reaction (D reaction (g) [In the formula, each symbol has the same meaning as above. ] reaction (h) [In the formula, R', R'', A, X and W have the same meanings as above.

R6 represents lower alkoxy, lower alkylthio, an optionally substituted amino group, or a cyano group.

1 Reaction (k) In formula 1, R1, R", A and X have the same meanings as above. W represents a halogen atom. Reaction (i) In formula 1, R', R", A and Same meaning. R2
represents a lower alkyl group. ] Reaction (N) [wherein R', R'', A, X and W have the same meanings as above.

] [wherein R', R3, R', A and X have the same meanings as above.

n represents O or l. 1 The above reaction (a) involves alkylation in the presence of a base in an organic solvent by the action of an alkylating agent (I[[).

For 1 mole of compound (I[), about 1 to 3 moles of base and about 1 to 3 moles of alkylating agent (I([)) are used, usually dimethylformamide, dimethylacetamide, dimethyl sulfoxide, acetonitrile, acetone, ethylmethyl. It is carried out in a solvent such as a ketone.

Such bases include sodium hydride, potassium t-butoxy, potassium carbonate, and sodium carbonate.

Such an alkylating agent (I[[) is a substituted halide (
For example, it is used as a chloride, bromide, iodide, etc.), but it may also be used as a substituted sulfonic acid ester (for example, methyl p-toluenesulfonate, etc.).

The reaction conditions vary depending on the combination of base and alkylating agent (II) used, but are usually 1-10% under water cooling to room temperature.
It is preferable to do this in about an hour.

In reaction (b), the cyano group substituted on the benzene ring of compound (Ia) is reacted with various azides in an organic solvent to convert it into the tetrazole compound (Ib).

1 to 3 azide compounds per 1 mole of compound (I a)
Usually used in molar quantities, dimethylformamide.

It is carried out in a solvent such as dimethylacetamide, toluene, or benzene.

Examples of such azide compounds include trialkyltin azide, triphenyltin azide, and hydrazoic acid.

When using an organic tin azide compound, the reaction is carried out in toluene or benzene for about 10 to 30 hours while heating under reflux.

Further, when reacting hydrazidic acid, sodium azide and ammonium chloride are used in about twice the molar amount of compound (Ia), and the reaction is carried out in dimethylformamide at about 100 to 130°C for about 1 to 3 days. During this time, it is preferable to accelerate the reaction by adding appropriate amounts of sodium azide and ammonium chloride.

In reaction (C), ester (Ic) is hydrolyzed in the presence of an alkali to obtain carboxylic acid (Id).

The reaction is usually carried out in a solvent such as an alcohol containing water (eg, methanol, ethanol, methyl cellosolve, etc.) using about 1 to 3 moles of alkali per mole of compound (I c). As such alkali, sodium hydroxide, potassium hydroxide, etc. are used. Furthermore, the reaction is carried out at room temperature to about 100°C.

It is preferable to wait for about 1 to 10 hours.

The reaction (d) involves intramolecular dehydration and ring closure of the anilide obtained by reducing the nitro group to form a benzimidazole derivative (
I).

The reducing agent is used in an amount of about 2 to 10 moles per mole of compound (IV). Examples of the reducing agent include metals such as iron, zinc, and tin, and the reaction can be carried out usually under acidic or alkaline conditions. Alcohols (e.g.
(methanol, ethanol, etc.), ethers (eg, dioxane, tetrahydrofuran, etc.), and acetic acid or hydrochloric acid are used alone or as a mixture.

Reaction conditions vary depending on the combination of reducing agent, solvent, and acid (or alkali) conditions used, but are usually from room temperature to 100 °C.
It is carried out for about 1 to 5 hours at about °C.

In this reaction, after the reduction reaction, it is preferable to heat at about 506 to 100° C. for about 2 to 3 hours under acidic conditions in order to cause a dehydration ring closure reaction.

Reaction (e) involves reacting the diamino compound (V) with various compounds in an organic solvent to perform a condensation ring-closing reaction and convert it into the benzimidazole compound (I).

Such compounds include carboxylic acids, aldehydes, orthoesters, iminoethers, iminothioethers, and the like.

Usually 1-1 of these reagents are added to 1 mole of compound (■).
The reaction is carried out in an organic solvent using an excess of about 0 mol, but the reagent can also be used as a solvent.

Such solvents vary depending on the reagent used, but include alcohols (methanol, ethanol, etc.).

Cellosolves (methyl cellosolve, ethyl cellosolve, etc.), halogenated hydrocarbons (chloroform, methylene chloride, etc.), ethers (dioxane, tetrahydro-7rane, etc.), aromatic hydrocarbons (benzene, toluene), acetonitrile, dimethylformamide, etc. can be used.

In addition, acids (hydrochloric acid, sulfuric acid, p-toluenesulfonic acid, etc.) or bases (triethylamine,
It can also be carried out by adding pyridine, sodium methoxide, sodium ethoxide, potassium carbonate, etc.).

The reaction conditions vary depending on the reagent used, but it is usually preferable to wait at room temperature to about the boiling point of the solvent for about 1 to 10 hours.

Reaction (f) involves hydrolyzing ester (Ie) in the presence of an alkali to obtain carboxylic acid (If).

About 1 to 3 moles of alkali are used per mole of compound (I e), and the reaction is usually carried out in a solvent such as an alcohol containing water (eg, methanol, ethanol, methyl cellosolve, etc.). As such alkali, sodium hydroxide, potassium hydroxide, etc. are used.

The reaction conditions are preferably room temperature to about 100° C. and about 1 to IO hours.

Reaction (g) is to obtain a hydroxymethyl compound (Ig) by reducing the carboxylic acid ester (Ie).

The reducing agent is used in an excess of about 1 to 5 moles per 1 mole of compound (Ie). Examples of such reducing agents include lithium aluminum hydride and sodium borohydride. When using the former, an ether-based solvent (such as tetrahydro7ran, dioxane, ethyl ether, etc.) is usually used as the solvent, and the
Allow a time window of ~20 hours. When using the latter, the solvent may be ether-based (tetrahydrofuran and dioxane) or alcohol-based (ethanol, propatool, etc.).

butanol, etc.), and methanol is preferably added as appropriate to promote the reaction. The reaction is carried out at room temperature to about the boiling point of the solvent over a time window of about 1 to 20 hours, preferably at about 50° C. to about the boiling point of the solvent.

In reaction (h), compound (Ig) is reacted with a saponification reagent in an organic solvent to obtain compound (Ih).

Examples of such organic solvents include halogenated hydrocarbons such as dichloromethane and chloroform dichloroethane, ethyl ether, and tetrahydrofuran.

Ethers such as dioxane are used.

Further, as the halogenating reagent, thionyl chloride, phosphorus oxychloride, etc. can be used. Among these, thionyl chloride is preferred because post-treatment after the reaction is simple. The reaction is usually
It is preferable to carry out a time window of about 1 to 10 hours at room temperature to about the boiling point of the solvent.

Reaction (1) reduces the halogen compound (Ih) to form the methyl compound (
11).

As reducing agents, metal hydrides (eg, organotin hydrides, etc.), metal hydride complexes (eg, sodium aluminum hydride, sodium borohydride, etc.), metals and their salts (eg, zinc, copper, sodium).

Lithium, etc.) can be used. Among them, metal hydrides (e.g., Ph5Sn, Bu, SnH, etc.)
When using a tin hydride compound, it is preferable to use about 1 to 3 times the molar amount of the tin hydride compound in an aromatic hydrocarbon solvent (eg, benzene, toluene, etc.) and carry out the reaction for about 3 to 10 hours at about the boiling point of the solvent. Iodo and bromine compounds react quickly, but in the case of chlorine compounds, peroxides (e.g. perbenzoic acid) and azobisisobutyronitrile (AIBN) are used to accelerate the reaction.
It is preferable to add

Reaction (J) involves reacting a halogen compound (I h) with a nucleophile in an organic solvent to obtain a substituted compound (I k).

Examples of such organic solvents include alcohols (e.g., methanol, ethanol, propatool, butanol, etc.), ethers (e.g., tetrahydrofuran, dioxane, etc.)
, halogenated hydrocarbons (e.g. dichloromethane, chloroform, dichloroethane, etc.).

Acetonitrile, dimethylformamide, and the like can be used. The solvent used is preferably selected appropriately depending on the nucleophile used. Examples of such nucleophiles include alcohols such as methanol and ethanol, thiols such as methyl mercaptan, amines such as alkyl amines and aralkyl amines, and cyanides such as potassium cyanide.

During the reaction, use a suitable base (e.g., potassium carbonate, sodium carbonate, sodium hydride, sodium alkoxide, etc.)
Preferably, it is carried out in the presence of

Although the reaction varies depending on the combination of reagents and solvents, it is usually preferably carried out under water cooling at about 50° C. for about 1 to 10 hours.

Reaction (k) converts nitrile (Ik') to ester (I(2)
It is converted into .

Nitrile (Ik') is mixed with alcohol (e.g., methanol, ethanol,
It is convenient and suitable to carry out the reaction for about 3 to 20 hours at about 50° C. to the boiling point of the solvent in a solvent (propertool, butanol, etc.). The alcohol used at this time functions as a solvent and a reaction reagent. Although iminoether is produced as an intermediate in the reaction, it is preferable to obtain the ester without isolating it.

Reaction (2) involves reacting carboxylic acid (If) with alcohol to obtain ester (Im).

The reaction is usually carried out in the presence of an acid catalyst using a reacting alcohol (eg, methanol, ethanol, propatool, butanol, etc.) as a solvent. Such catalysts include:
Mineral acids such as hydrochloric acid and sulfuric acid, or organic acids such as p-toluenesulfonic acid, etc. can be used.

The reaction conditions are preferably about 5 to 20 hours at about the boiling point of the solvent.

After completion of the reaction, the reaction products obtained in reactions (a) to (12) as described above can be easily isolated by conventional isolation and purification methods, such as column chromatography and recrystallization. I can do it.

In addition, these compounds (I) can be prepared by conventional methods into salts with physiologically acceptable acids or bases, such as salts with inorganic acids such as hydrochlorides, sulfates, and nitrates; It can be converted into salts with organic acids such as acid salts and maleates, salts with alkali metals such as sodium salts and potassium salts, and salts with alkaline earth metals such as calcium salts.

Among these compounds, compound (II), (III)
, (IV) and (V) are, for example, (1) P, N, Preston, ”The
Chemistry ofHeterocyclic
Compounds' Vol, 40. ed.

by P, N, Preston, Tohn Wi
lcy & 5oz.

New York (1981), pp, l 286
゜(2) A, Hunger, J, Kebrle
, A., Rossi and K.

Hottmann, He1v, Chim, Act
a, 43.1032 (1960).

(3) R, C, De Se1m5. J, Org.
Chem, +27.2163 (1962).

(4) A, F, Ca5y and J, Wri
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(C), chain, 1511° (5) O, Meth-Cohn, H, 5uschi
tzky ancl M, E.

5utton, J, Chem, Soc, (C)
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Zhenov, Ch, Sh, Kadyrov a
ndP.

Kurbanov Khim, Geterotsi
kl, 5oed1n,.

1972, 641° (7) N., Vinot, But! , Soc,
Chim, Fr, 1966+(3) M, W,
Partridge and H.A. Turner
, J.

Chem, Sac, 1958.2086(9)
R, E, Lyle and J, L, Lamat
Tina, J, Org.

Chem,, 40. 438 (1975) (10)
S, H, Dandegaonker and C,
R, Revankar.

J, Karnatak Univ,, 6.25(1
961Xcf, CA, 10023b).

(11) Y, Kanaoka, O, Yonemi
Tsu, K., Tanizawa and Y.
Ban, Chem, Pharm, Bull,...
12. 773 (1964).

(12) J, Preston, W, F, De
vinter and W, L.

Hofferbert, Jr., J. Heterocy.
cl, Chem.

6, 119 (1969) (13) B, C, B15hop, A, S,
Jones and J, C.

Tatlow, J. Chem, Soc.
1964.3076 (14) H, Depoorter
, G., G., Van Mierlo, M.
J.

Libeer and J, M, Nys, Be1
g, 595.327°Mar, 23. 1961 (
cf. CA, 58.9085a (1963)).

(15) H, J, J, Loozen and E
, F., Godefroy, J.Org., Che.
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(16) N, 5uzuki, T, Yam
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Jones, G., Gal and M., Sle.
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0.259 (1965).

(13) M, 1taya, Yakugaku Z
Asshi, 82.1 (1965).

(19) 1. Ganea and R, Tara
nu, 5tud, UnivBabes-Bolya
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cf-CA, 67, 32648s (1967)).

(20) D, Jerchel, H, Fisch
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Ann, Chem, 162 (1952).

(21) N., S., Kozlov and M.
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Vestsi Akad, Navuk Be1arus
,SSR,Ser.

Khim, Navuk 1967, 89 (cL CA
, 69.49507p) (22) J, B, Wr.
light, Chem, Rev,, 48.397 (
1951).

It can be synthesized by the method described in et al. or a method similar thereto.

Further, the raw material compound (IV) is, for example, 5eno, S, Hagishita, T, 5a.
to and K, KuriyamaJ, Che
m, Sac,, Perkin Trans, 1.1
Compound (Vl) synthesized by the method described in 984.2013 etc. or a method analogous thereto, by a method similar to reaction (a) or a method analogous thereto (for example, the reaction formula (
m)) can be easily obtained.

Further, the starting compound (V) can be synthesized by the method described in reaction (n) or a method analogous thereto.

In addition, the raw material compounds (XIV) and (XV) are reacted (0
) or a method similar thereto.

Reaction (m) In formula 1, A, R', R'', R', X and 0 have the same meanings as above. W represents a halogen atom.1 Reaction (n) X ■ ■ In formula 1, A, R ", R" and X have the same meanings as above.

W represents a halogen atom. 1 Reaction (o) xv 1 [In the formula, A, R1, R', R'', R' and , 2 is -Q-,
-NH- or -5-. ]The reaction (m) is the reaction (c
) Compound (Vl) is alkylated to obtain N-alkyl derivative (IV).

In reaction (n), 0-nitrobenzoic acid derivative (■
) with a halogenating reagent (e.g., thionyl chloride).

The acid azide produced by reacting with an azide (e.g. sodium azide) is easily converted into isocyanate (X).
becomes. When incyanate (X) and t-butanol are heated and reacted, carbamate (II) can be obtained in high yield. Carbamate ester (II) is a benzoic acid derivative (■) and diphenylphosphoryl azide (D P P
It can also be obtained by subjecting A) to a heating reaction in t-butanol. The carbamate ester (II) thus obtained was alkylated in the same manner as in reaction (,), and the resulting compound (II) was treated with a reducing agent (e.g., Raney nickel, stannic chloride, iron-hydrochloric acid, and hydrazine-hydrochloric acid). (ferric iron, etc.), the diamino compound (V) can be obtained in high yield.

In reaction (0), diacylamino is produced by heating the diamino compound (V) with an acid chloride (e.g., chloroacetic acid chloride, 2-chloropropionic acid chloride, etc.) in the presence of a base (e.g., triethylamine, pyridine, etc.). A benzimidazole derivative (XrV) can be obtained in high yield by subjecting the compound to a heated reaction with an acid (hydrochloric acid-ethanol, etc.). Chloride (XIV) was treated with various nucleophiles (
(e.g., sodium methoxide, sodium ethoxide, methylamine, ethylamine, sodium thiomethoxide, sodium thioethoxide, etc.), the substitution products (X V) are obtained in high yields. Compound (XV) thus obtained can be used to synthesize target compound (I) through reactions (b) and (c).

Compound (1) and its salts produced in this manner strongly suppress the vasoconstrictive and blood pressure increasing effects caused by angiotensin H with low toxicity, and are effective in animals, especially mammals (e.g.
It has a blood pressure-lowering effect on humans, dogs, rabbits, rats, etc.) and can be used not only as a treatment for hypertension, but also for cardiovascular diseases such as heart disease, stroke, kidney disease exhibiting proteinuria, and arteriosclerosis. It is useful as a drug. When used as such pharmaceuticals, compound (I) and its salts may be used as such or mixed with appropriate pharmacologically acceptable carriers, excipients, and diluents to form powders, granules, tablets, capsules, and injections. It can be administered orally or parenterally in the following dosage forms.

The dosage varies depending on the target disease, symptoms, subject, administration method, etc., but when administered as a treatment for adult essential hypertension, the daily dose is 0.1-50 mg for oral administration, and 0.0 mg for intravenous injection. .1-3 mg is preferably administered in 2-3 divided doses.

(Example) The present invention will be explained in more detail below using formulation examples, working examples, experimental examples, and reference examples, but it goes without saying that these do not limit the present invention.

Examples of abbreviations used in this specification are listed below.

Me: methyl, Et: ethyl, Pr: proyl.

Bu Nibutyl, Pen: Bentyl, Tet: Tetrazolyl, THF: Tetrahydrofuran, DMF: Nidimethylformamide, Ph: Phenyl, Ac Niacetyl Formulation Example The compound (I) of the present invention can be used to treat, for example, hypertension, heart disease, etc.
When used as a therapeutic agent for circulatory system diseases such as stroke,
For example, it can be used according to the following formulation.

■, Capsule (1) 2-butyl-1-[[2'-(LH-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylic acid 0 mg (2) Lactose 90 mg (
3) Microcrystalline cellulose 70mg (4
) Magnesium stearate 10mg 1 capsule 180mg After mixing 172 of (1), (2), (3) and (4), it is refined. Add the remaining (4) to this and encapsulate the whole in a gelatin capsule.

2. Tablets (1) 2-butyl-1-[[2'-(I H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylic acid OLI 1 g (2) Lactose 35 mg (
3) Cornstarch 150mg (4
) Microcrystalline cellulose 30mg (5)
Magnesium stearate 5II 1g 1 tablet 230+ng (1), (2), (3), (4) 273 and (5)
After mixing 1/2 of the mixture, it is granulated. The remaining (4) and (
5) is added to the granules and pressure molded into tablets.

3. Injection (1) 2-Butyl-1-[[2'-(IH-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylic acid disodium salt
10mg (2) Inojit
100mg (3) benzyl alcohol
20 mg 1 ampoule 130 mg Dissolve (1), (2), and (3) in distilled water for injection so that the total amount is 2-, and seal it in an ampoule. The entire process is performed under aseptic conditions.

4. Capsule (1) l -(cyclohexyloxycarbonyloxy)ethyl 2-butyl-1-[[2'-(I H-tetrazol-5-yl)biphenyl-4yl]methyl]
Benzimidazole-7-carpoxylate 0cag (2) Lactose 90mg (
3) Microcrystalline cellulose 70mg (4
) Magnesium stearate 10mg 1 capsule 180mg After mixing 172 of (1), (2), (3) and (4), it is granulated. Add the remaining (4) to this and encapsulate the whole in a gelatin capsule.

5. Tablets (1) l-(cyclohexyloxycarbonyloxy)
Ethyl 2-butyl-1-[[2'-(IH-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carpoxylate 10+og (2) Lactose 35 mg (
3) Cornstarch 150mg (4
) Microcrystalline cellulose 30mg (5)
Magnesium stearate 5mg 1 tablet
230mg (1), (2), (3), 273 of (4) and 1/2 of (5) are mixed and then granulated. The remaining (4
) and (5) are added to the granules and compressed into tablets.

6. Capsules (1) Pivaloyloxymethyl 2-butyl-1-[[
2'-(IH-tetrazol-5-yl)biphenyl-
4-yl]methyl]benzimitazole-7-carpoxylate 0 mg (2) Lactose 90+g (
3) Microcrystalline cellulose 70mg (4
) Magnesium stearate 10 mg 1 capsule 180 mg (1), (2) and 1/2 of (3) and (4) are mixed and then granulated. Add the remaining (4) to this and encapsulate the whole in a gelatin capsule.

7. Tablets (1) Pivaloyloxymethyl 2-butyl-1[[2
'-(IH-tetrazol-5-yl)biphenyl-4
-yl 1 methyl 1 benzimidazole-7-carpoxylate 0 mg (2) Lactose 35 Mg (
3) Cornstarch 150mg (4
) Microcrystalline cellulose 30mg (5)
Magnesium stearate 5mg 1 tablet
230mg (1), (2), (3), (4) 273 and (5)
After mixing 172, it is granulated. The remaining (4) and (
5) is added to the granules and pressure molded into tablets.

Reference Example 1 27-butyl-5-methoxybenzimidazole 4-methoxy-〇-7 2-diamine (4.4 g) and ethylvaleroimidate hydrochloride (4.6 g) in ethanol (50 g)
m) Triethylamine (5.7 g) was added to the solution and stirred at room temperature for 2.5 hours. The reaction solution was concentrated, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried, and concentrated. After the obtained residue was purified by silica gel chromatography, the obtained crystals were recrystallized from isopropyl ether to obtain needle crystals (2.7 g, 53%).

Melting point 95-96℃ Elemental analysis value C (%) as C1zH+sN*O
H (%) N (%) Calculated value: 70.50, 7.89;
13.71 Actual value: 70.68, 7.95
i 13.72'HNMR (CDCI2sM:
0.93C3H,t), 1.2 2-0(4H,m
), 2.89 (2H, t), 3.81 (3H, s),
6.84 (LH, q).

7.02 (18, d), 7.42 (IH, d) The following compounds were synthesized in the same manner as in Reference Example 1.

Reference Example 2 2-Butyl-5-chlorobenzimidazole colorless needle crystals, melting point 149-150°C, yield 78% Elemental analysis CI
rH13CΩN, as C (%) H (%) N
(%) Calculated value: 63.31; 6.28;
13.42 Actual value: 63.35: 6.4
6; 13.30'H-NMR (CDCQ3) δ
: 0.90 (3B, t), 1.20-1゜60 (2
H, m), 1.67-2.00 (2H, m), 2.
92 (2H, t), 7°17 (IH, m), 7.3
8-7.52 (2H, m) Reference Example 3 2-butyl-5-nitrobenzimidazole colorless crystals,
Melting point t4o = 41°C, yield 77% Reference example 4 2-propylbenzimidazole 0-phenyl diamine (2.2 g) and butyric anhydride (4,
7g) was stirred at 110°C for 4 hours, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with hydrogenated sodium hydroxide solution, dilute hydrochloric acid and water, and then dried.

The solvent was evaporated and the residue was dissolved in 3N hydrochloric acid (35ml) for 1.5 hours.
The mixture was heated under reflux for 5 hours. The reaction solution was made alkaline with 6N caustic soda water, and the precipitated crystals were recrystallized from ethyl acetate-hexane to obtain colorless plate crystals (0.9 g, 38%).

Melting point 160-162℃ 'H-NMR (90MHz, CDCQ,) δ: 1.0
0 (3H, t) 1.88 (2H, 5e (six doublet)),
2.91 (2H, t), 7.10-7.35 (2H,
m), 7.45 7.70 (2H, m), 8.30
(IH, br s) Reference Example 5 2-Pentylbenzimidazole ○-Pentylbenzimidazole (2.2 g) and triethylamine (2.0 g) were added to a methylene chloride solution (20 m) while stirring under ice cooling. Loyl chloride (2.3 g) was added dropwise. After stirring at room temperature for 3 hours, the reaction solution was washed with saturated soda water and water, and dried. 3N-hydrochloric acid was added to the residue obtained by distilling off the solvent, and the mixture was heated under reflux for 1.5 hours. The reaction solution was made alkaline with a 6N aqueous solution of caustic soda, and the precipitated crystals were recrystallized from ethyl acetate-hexane to obtain colorless needles (1.5 g, 47%).

Melting point 161-162℃' H-NMR (90MHz, CD CQ
s) δ: 0.86 (3H, t).

1.1-1.6 (4H, m), 1.7-2.0 (2H
, m), 2.92 (2H, t).

7.1-7.3 (28, m), 7.5-7.7 (2H
, m) Reference Example 6 A solution of 2-butyl-1-[(2'-noanobiphenyl-2-butylbenzimidazole (0.87 g) in dimethylformamide (DMFX 5 mJ) was cooled with ice and added with sodium hydride (60% After adding 0.24 g of oil and stirring for 10 minutes, 4-(2-cyanophenyl)benzyl chloride (1.1, g) was added and stirred for 1.5 hours.Water was added to the reaction solution, and ethyl acetate was added. The extract was extracted with water, washed with water, and concentrated under reduced pressure.The product was purified by silica gel column chromatography to obtain the desired product as a colorless oil (1.8 g, quantitative).

') I-NMR (CDCI23) δ: 0.90 (3H
,t), 1.2-1゜6(21(,m), 1.65
-2.00 (2H, m), 2.85 (2H, t),
5゜37(2H,s), 7.0-7.9(121(,
m) The following compound (Reference Example 7-16) was prepared in the same manner as in Reference Example 6.
) was obtained.

Reference Example 7 2-Butyl-1-[(2'-cyanobiphenyl-4-yl)methyl 1-6-medoxybenzimidazole Yield 48% Melting point Oil 'HNMR (200MHz, CDCJ) δ: 0.93 (
3H, t).

1-14 1.53 (2H, m), 1.76-1.9
1 (2H, m), 2.83 (2H, t), 3.81
(3H,s), 5.37(2H,s), 6.70(
IH, d).

6.89 (LH, dd), 7.17 (2H, d),
7.41-7.53 (4H, m).

7.61-7.68(21(,m), 7.77(It
(,dd)IR(neat)cm-': 2220.
1620.1595.1520.14g5゜1460,
1415.1350.1275.1260.1215.
11751135, 1105.1025.930.81
5.765 Reference Example 8 Sol yield 44% Melting point Oil 'H-NMR (200MHz, CDCQ3) δ: 0.
93 (3H, t).

1.35-1.53 (2H, m), 1.76-1.9
2(21(,m), 2.85(2H,t), 3.8
6 (3H, s), 5.38 (2B, s), 6.86
(LH, dd) 7.11 (IH, d), 7.15 (2
H, d), 7.29 (IH, d), 7.417.5
3 (3H, m), 7.64 (IH, dt), 7.7
7 (LH, dd) I R (neat) cm”: 222
0. 1620. 1595. 1485. 1440
゜1415, 1345. 1275. 1200.
1160. 1030.835° Reference Example 9 Yield 48% Melting point Oil 'HNMR (200MHz, CDCQs) δ: 0.9
4 (3H, t).

1.35-1.54 (2H, m), 1.77-1.9
2 (2H, m), 2.87 (2H, t), 5.40
(2H, s), 7-12-7.27 (4H, m),
7.42-7.55 (4H, m), 7.65 (LH,
q), 7.75-7.80(2H,m)IR(ne
at) am”: 2220.1510.1460.14
00.760 Reference Example 10 2-Butyl-6-chloro-1-[(2'-cyanobiphenyl-4-yl)methyl 1-benzimidazole Melting point 124
-125°C (yield 35%) 'HNMR (200MHz, CDCQs) δ: 0.9
4 (3H, t).

1.35-1.54 (2H, m), 1.77-1.9
2 (2H, m), 2.85 (2H, t), 5.37
(2H, s), 7.14 (2H, d), 7.20-
7.25 (2H, m), 7.41-7.55 (4H,
m), 7.61-7.70 (2H, m).

7.77 (IH, d) I R (KBr) c+a-': 2220.1620.
1595.1485.1440°1415, 1345.
1275.1200.1160.1030.835° Reference Example 11 Reference Example 13 Yield Quantitative Melting Point Oil 'HNMR (200 MHz, CDCl25) δ: 1.
04 (3B, t).

1.82 2.00 (2H, +o), 2.86 (2H
, t), 5.42 (2H, s).

7.15 (2H, d), 7.21-7.29 (3H,
m), 7.40-7.53 (4H, +11), 7.
59 7.68 (IH, m), 7.73 7.81 (
2H,m)IR(neat)cm-”: 2220.
1510.1480.1455.1410°760,7
40 Reference example 14 Yield 45% Melting point Oil Reference example 12 Yield 43% Melting point Oil yield Quantitative melting point Oil "HNMR (200 MHz, CDCl25) δ: 0.
88 (3B, t).

1.23-1.44 (4H, m), 1.80-1.9
5(21(,m), 2.87(2H,t), 5-4
3 (2H, s), 7.16 (28, d), 7.21
-7.29 (3H, +a), 7.41 7-53 (4
H, m), 7.60 7.68 (IH, m).

7.74-7.82 (2H, m) IR(neat) cm-': 2220. 2510
．． 1480. 1455. 1410°760,74
0 Reference Example 15 Yield Quantitative Melting point Oil 'H-NMR (200MHz, CDC et al.) δ: 5.4
4 (2H, s).

7.26-7.34 (4H, m), 7-41-7.
55 (4H, +m), 7.60-7.68 (IH,
■), 7.76 (IH, dd), 7.83-7.8
7 (IH, m).

8.01(IH,s) IR(neat)am-”: 2220.1500.
1480.1460.1440°1365, 12B5.
760.740 Reference Example 16 Yield 41% Melting point 235-236°C "H-NMR (200MHz, DMS 0-ds) δ:
0.87 (3H, t), 1.1-1.5 (2H,
m), 1.70 (2H, quin,), 2.82
(2) f, t), 5.49 (2H, s), 7.05
(4H, s), 7-13-7.22 (2H, m),
7.46-7.71(6H,+a)IR(KBr)c
m-': 1510. 1460. 1415.755
．． 760 Reference Example 17 Zimidazole 2-butyl-1-(2'-cyanobiphenyl-4-yl)methylbenzimidazole (1,8 g), sodium azide (0,98 g) and ammonium chloride (0,
80g) was stirred in DMF (6m) at 110°C for 5 days. During this time, add sodium azide (1.6 g).

Ammonium chloride (1.3g) and DMF (5m) were added. Water and ethyl acetate were added to the reaction solution, and the precipitated crystals were collected by filtration. The organic layer of the filtrate was washed with water, dried, and concentrated under reduced pressure to obtain crude crystals. Recrystallized from ethyl acetate-methanol together with the previous crystals to obtain colorless prismatic crystals (
2 g of OJ, 41%) was obtained.

Melting point 235-236℃ Elemental analysis value C (%) H (%) N (%) Calculated value, 73.51, 5.92;
20.57 Actual value: 73.42, 5.90
20.87'HNMR (200MHz, DMSO
ds) δ: 0.87 (3H, t), 1.26 1.
45 (2H, m), 1.62-1.77 (2H, m)
.

2.82 (2H, t), 5.49 (2H, s), 7
．． 05 (4H, s), 7.13-7.22 (2Lm)
, 7.46-7.71(6H,m)IR(KBr)
c+n″″’: 1510.1460.1415.77
5.760° The following compound was obtained in the same manner as in Reference Example 17.
;.

Reference Example 18 Melting point 146-I49℃ (decomposition) Elemental analysis value CzaH*aNa0.215H, as O, C (%) H (%) N (%) Calculated value: 70.06; 6゜06;
1g, 85 actual value: 70.27; 6.0
3; 18.42'HNMR (200MHz, D
MSOda) δ: 0.87 (3H, t), 1.2
5 1.44 (2H, m), 1.60-1.75 (
2H, m) 2.78 (2H, t), 3.77 (3H,
s), 5.45 (2H, s), 6.80 (IH, q
), 7.01 (2H, d), 7.06 (2H, d)
, 7.13 (IH, d).

7.35 (IM, d), 7.47-7.70 (4H,
m) I R (KBr) cm”: 1490.1450.
1440.1195.1155°1020, 825.
755 Reference Example 19 Melting point 243-244℃ (decomposition) Elemental analysis value Cz @ Hx * N * C as O
(%) H (%) N (%) Calculated value: 71.21; 5.98, 19
．． 16! i! ! Measured value: 70.98: 5.9
6: 19.41'HNMR (200MHz, D
MS Oda) δ: 0.86 (3H, t), 1.2
4-1.43 (2H, m), 1.58-1.73 (2
H, +o) 2.75 (2H, t), 3.75 (3) 1
．． s), 5.45 (2H, s), 6.78 (1H,
q), 7.05 (5H, m), 7.43-7.70
(5H,m)IR(KBr)cm-'+ 1615
．． 1490. 1450. 1260. 1220゜1020, 825.810.745 Reference example 20 Melting point 249-250℃ (decomposition) Elemental analysis value CzsHzsC4Ng・1/2HzO, C (%) H (%) N (%) Calculated values:
6δ, 44; 5.35 i 18.59
Actual value: 66.55; 5.13;
18.37'H-NMR (200MHz, DMSO-
d,) δ: 0.87 (3H, t), 1.26 1.
44 (2H, ++), 1.61-1.76 (2H, m
).

2.81 (2H, t), 5.50 (2H, s), 6
．． 99-7.09 (4H, m).

7.20(l)1. q), 7.47-7.70 (7H
,o+)IR(KBr)am-': 1500.14
50.1410.1000.785° Reference Example 2I 2-Butyl-6-chloro-1-[[2'-(IHtetrazol-5-yl]biphenyl-4-ylco) Melting point 21
6-217°C Elemental analysis value CxsHxs CQN s as C (%)
H (%) N (%) Calculated value: 67.79; 5.23;
18.97 Actual value: 67.41; 5.1
9; 19.02'HNMR (200MHz, D
MSOds) δ: 0.86 (3H, t), 1.25-
1.43 (2H, m), 1.60-1.75 (28,
m) 2.79 (2H, t), 5.51 (2H, s),
7.01 (2H, d), 7.08 (2H, d),
7.18 (IH, q), 7.49-7.72 (6) 1
．． m) I RCKBr) cm-': 1460.141
0.755 Reference Example 22 Yield 51% Melting point 238-239℃ Elemental analysis C2+H+aNi bow 15H20 as C(
%) H (%) N (%) Calculated value: 70.85; 4.64;
23.61 Actual value: 70.75; 4.4
0, 23.41'HNMR (200MHz, DM
S Odi) δ: 5.51 (2H, s), 7.07
(2) (, d), 7.19-7.28 (4H, m),
7.49-7.71 (6H, m), 8.42 (IH
,s)IR(KBr)cm-': 1505.146
0.1375.1290.1265°1230, 11
95.1145. 1035.965.945.820
．． 775°760, 750.740 Reference Example 23 Yield 70% Melting point 239-240°C (decomposition) Elemental analysis value C2aHzxNa'l/2MeOH・31
5H,O as C (%) H (%) N (%) Calculated value: 69.85; 6.03,
19.95 Actual value: 69.88; 6.01
; 19.79'HNMR (200MHz, DM
S Oda) δ: 0.96 (3H, L), 1.67
-1.85 (2H, m:), 3.05 (2H, t),
5.68 (2H, s), 7.09 (2H, d),
7.17 (2H, d), 7.40-7.77 (8H,
m) I R (KBr) cm”: 1505.14g0.
1460. 1415. 1405°760, 74
5 Reference Example 24 Yield 41% Melting point 208-209°C Elemental analysis value C**HxmNa as C (%) H (%) N (%) Calculated value: 73.91; 6.20;
19.89 Actual value: 73.67; 6.19
; 20.00'H-NMR (200MHz, DM
SOds) δ: 0.84(3H,t), 1.27-
1.34 (4H, m), 1.64-1.78 (2H,
m).

2.81 (2H, t), 5.49 (2B, s), 7
．． 04 (4H, s), 7.12-7.20 (2H, m
), 7.46-7.69(6H,m)IR(KBr
)cm”: 1510.1460.1410.745 Reference Example 25 2-Butylbenzimidazole (0.52g) in DMF
(4Wtl) while cooling the solution with ice, add sodium hydride (
60% oil-based, O, 13 g) was added and stirred for 20 minutes.

After adding methyl 2-(4-bromomethylphenyl)benthia) (1.0 g) and stirring at room temperature for 1.5 hours, water was added and the mixture was extracted with ethyl acetate.

The residue obtained by drying the solvent and concentrating under reduced pressure was purified by silica gel column chromatography to obtain a colorless oil (1,
2 g, quantitative) was obtained.

'HNMR (90 MHz, CD Cl2s) δ: 0.
92 (3H, t).

1.25-2.00 (4H, +a), 2.87 (2H
, t), 3.60 (3H, s).

5.36 (2H, s), 7.05 (2H, d), 7
．． 15-7.60 (8H, m).

7.65-7.9 (2H, n+) I R (neat) cm-': 1725.1455.
1405.1280.1245780, 755.740 Reference Example 26 -yl)methylphenyl 1-benzoate methyl 2-[4-(2-butylbenzimidazole-
1-yl)methylphenyl]benzoate (1,2g)
was heated under reflux for 3 hours in a 1N-NaOH solution (4,5it12) and methanol (10Wf).The residue obtained by concentrating the reaction solution was dissolved in water, and after washing with ether, I
N=Acidify with hydrochloric acid. The precipitated crystals were collected by filtration and recrystallized from ethyl acetate-methanol to give colorless crystals (0.64
g, 53%) was obtained.

Elemental analysis value C*5H2aNzOx (%)
H (%) N (%) Calculated value: 78.10; 6.29,
7.29 Actual value: 77.99; 6.36
, 7.22'HNMR (200MHz, CDCl
23) δ: 0.63 (3H, t).

0.99-1.17 (2H, m), 1.34-1.4
9(2H,m), 2.62(21(,t), 5.3
2 (28, s), 7.04 (2H, d), 7.18
-7.55 (8H, m), 7.66 (IH, dd),
7.92 (LH, dd) I R (KBr) cm-':
1690.1610.1600.1515.1465
゜1420, 1300.1250.1140.1090
．． 1005.820°765,750 Reference Example 27 Reference Example 28 Methyl 3-nitro-2-(N-valerylamino)benzoate (2.8 g) was added to a mixture of concentrated hydrochloric acid (5.3d) and methanol (35d). After adding iron powder (1.7 g) little by little while stirring at room temperature, the mixture was heated under reflux for 8 hours. Insoluble matter was filtered off, the filtrate was concentrated, and water and ethyl acetate were added to the resulting residue. The aqueous layer was made alkaline with a 6N caustic soda aqueous solution, extracted with ethyl acetate, and the organic layers were combined, washed with water, and dried. The solvent was distilled off, and the residue was purified by silica gel column chromatography. The obtained crystals were recrystallized from isopropyl ether to give colorless needles (1.6 g, 70%).

Melting point 97-98°C 'HNMR (200MHz, CD Cm3) δ: 0.
93 (3H, t).

1.37-1.56 (2H, m), 1.80-1.9
5 (2H, m), 2.96 (2) 1. t), 4.0
0 (3H, s), 7.26 (LH, t), 7.85
(LH.

dd), 7.91 (IH, d), 10.13 (IH
,br s) Methyl 2-butylbenzimidazo-7carpoxylate (l, 5 g) in DMF (15d
) solution of sodium hydride (60% oil, 0.13 g)
was added under water cooling and stirred for 20 minutes, then 4-(2cyanophenyl)benzyl chloride (1.5 g) was added and further stirred at room temperature for 5 hours. Water was added to the reaction solution, extracted with ethyl acetate, and the organic layer was washed with water.

Dry. The solvent was distilled off, and the residue was purified by silica gel column chromatography to give a pale yellow oil (2.3 g,
82%).

'H-NMR (90MHz, CD Cff5)+t:
0-94(3)1. t).

1.37-1.55 (2H, m), 1.78 1.9
3 (2H, m), 2-96 (2H, m), 4.05
(3H,s), 5.46(2H,s), 7.12(
2H.

d), 7.25 (IH, t), 7.39-7.52
(5H, m), 7.64 (lH, dt), 7.76
(IH, d), 7.95 (lH, dd) I R (ne
at) Cm-': 2220.1710.1510.1
480.1435°1405.1350,1290,1
245,1215.1190.1130 Reference Example 29 Methyl 2-butyl-1-[(2'-cyanobiphenyl-4-yl)methyl]benzimidazole-4-carboxilade (2.3 g), sodium azide (5, 3g
) and ammonium chloride (4.4 g) in DMF (20
+a12) and stirred at 110-120°C for 26 hours. After adding water and ethyl acetate to the reaction solution, it was made acidic with concentrated hydrochloric acid. The precipitated crystals were collected by filtration and recrystallized from methanol-ethyl acetate to obtain colorless needle crystals (0.22 g, 9%).

Melting point 223-224℃ (decomposition) Elemental analysis value C (%) H (%) N (%) Calculated value: 68.72; 5.68;
17.81 Actual value: 68.69; 5.68
; 17.57'H-NMR (200MHz, D
MS○-aa) δ: 088 (3H, t), 1.2
8-1.47 (2H, m), 1.60-1.75 (
2H, m) 2.88 (2H, t), 3.89 (3H,
s), 5.56 (2H, s), 7.01 (2H, d
), 7.07 (2H, d), 7.27 (18, t)
, 7.47-7.66 (4H7■), 7.72-7
．． 77(2H,+)IR(KBr)cm-': 1
710. 1460. 1435. 1410. 12
95°1140, 765 Reference Example 30 The same reaction as in Reference Example 29 was carried out, and after adding water and ethyl acetate to the reaction solution, it was made acidic with 6N-hydrochloric acid. The precipitated crystals were filtered off, and the organic layer was separated from the filtrate, washed with water, dried, and concentrated to dryness. The residue was purified by silica gel column chromatography, and the resulting crystals were recrystallized from methanol-chloroform to give colorless prism crystals (0.37 g, 15%
) was obtained.

Melting point 235-236℃ Elemental analysis value Czsl (C (%) H (%) N (%) as zsN70・l/2H20 Calculated value: 67.81; 5.69;
21.29 Actual value: 67.64; 5.6
8 i 21.05'HNMR (200MHz, D
MS Odi) δ: 0.89 (3H, t), 1.3
0-1.48 (2H, m), 1.65 1.80 (2
H, m).

2.90(2f(,t), 5.58(2H,s),
7.06 (4H, s), 7.30 (IH, t), 7
．． 48-7.74 (5H, m), 7.84 (IH, d
d), 9.28(2H,s) I R(KBr)am-': 1660.1610.1
565.1500.1465゜1420, 1390.1
350.1255.10B0.1070.1015°8
85, 800.775.750 Reference Example 31 Methyl 3-nitro-2-valerylaminobenzoate After dropping fuming nitric acid (7,M) into acetic anhydride (60m) under water cooling, concentrated sulfuric acid (0,2172) was added. added. Add methyl 2-valeryl aminobenthia (12 g) to the mixture.
was added and stirred at room temperature for 1 hour. After adding ice water, extraction was performed with ethyl acetate, and the organic layer was washed with water, dried, and concentrated. The resulting residue was purified by silica gel column chromatography, and the resulting crude crystals were recrystallized from isopropyl ether to obtain colorless needles (3.9 g, 28%).

Melting point 61-62℃ Elemental analysis CrsHIIIN so s C (%
) H (%) N (%) Calculated value: 55.71; 5.75;
9.99 Actual value: 55.72; 5.7
9, 9.83'HNMR (CDC4s)a:
0-95 (3H, t), 1.30-1.50 (2H, m
), 1.65-1.80 (2H, m), 2.46 (
2F1. t).

3.97 (3H, s), 7.30 (IH, t), 8
．． 10 (IH, dd), 8.22 (lH, dd) Reference Example 32 Methyl 3-nitro-2-valerylaminobenzoate (3.9 g), 4-(2-cyanophenyl)benzyl bromide (3° 8g) and Co, (2°1g) to D
Stir in MF (30 wfl) at room temperature for 15 hours. Water was added to the reaction solution, extracted with ethyl acetate, and the organic layer was washed with water and dried. The solvent was distilled off, and the resulting residue was purified by silica gel column chromatography. The obtained crude crystals were recrystallized from ethyl acetate-hexane to give colorless crystals (5,
1 g, 78%).

Melting point 129-130℃ Elemental analysis Cx y H! IN! C as Os
(%) H (%) N (%) Calculated value: 68.78; 5.34 i
8.91 Actual value: 68.84; 5°43;
8.87'HNMR (200MHz, CDC45) δ:
0.85 (3H4).

1.18-1.36 (2B, w+), 1.61-1.
76 (2H, m), 2.08-2.16 (2F, +w
), 3.67 (3H, s), 4.65 (IH, d)
, 4.96 (IH, d), 7.20 (2H, d),
7.38-7.50 (4H, 01), 7.56-7
．． 68 (2H, m), 7.75 (lH, d), 7.
98 (IH, dd), 8.10 (IH, dd) Reference Example 33 Methyl 2-butyl-1-[(2'-cyanobi722-4-yl)methyl]penzimitasole-7-carpoxy Latomethyl 2-[N-(2'-cyanobiphenyl-4-yl)methyl-N-valeryl 1-amino-3-nitropenzoate (5,14 g) was mixed with concentrated hydrochloric acid (4,0 d) and methanol (Ion). In addition to the liquid, iron powder (1.9 g) was added little by little while stirring.

After stirring at 70-80°C for 3 hours, insoluble matter was filtered off and the filtrate was concentrated. Ethyl acetate and saturated sodium chloride water were added, and the precipitated insoluble matter was filtered off. The filtrate was separated and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, dried and concentrated, and the resulting residue was recrystallized from ethyl acetate to obtain colorless needles (4.15 g, 90%).

Melting point 123-124℃ Elemental analysis value C*tH! C (%) as IN so z
H (%) N (%) Calculated value: 76.57; 5.95; 9.
92 actual measurement value: 76.44, 6.03;
9.67”HNMR (200MHz, CDCl23)
δ: 0.96 (3H, t).

1.38 1.57 (2H, m), 1.82-1.9
7 (2H, m), 2.92 (2H, t), 3.72
(3H,s), 5.82(2H,s), 6.97(
2H, d).

7.26(II(,t), 7.39-7.46(4H
, +n), 7.58-7.66 (28m), 7.7
5 (II, dd), 7.97 (LH, dd) r R (
KBr) cm-': 2220.1725.1480.
1440.14201400, 1280.1260.1
195.1140.1115.765°750,745 The following compound was obtained in the same manner as in Reference Example 31.

Reference Example 34 Methyl 2-butyrylamino-3-nitrobenzoate Melting point 64-65°C 'HNMR (90MHz, CDCMs) δ: 1.03
(3H, t).

1.57-1.97 (2H, m), 2.43 (2H,
t), 3.97 (3H, s).

7.20-7.43 (IH, m), 8.07-8.2
7 (2H, +o), 10.50 (lH, br s) I R (Nujol) Cm-': 3300.1725
．． 1690.15851535, 1510.1445.
1355.1265.1210.1115 Reference Example 35 Methyl 2-hexanoylamino-3-nitrobenzoate Melting point 74-75°C 'H-NMR (90 MHz, CD (1!3) δ: 0.
90 (3H, t).

1.23 1.90 (6) 1. m), 2.43 (2H
,t), 3.93(3H,s).

7.27 (IH, t), 8.03-8.27 (2H, m
), 10.30 (IH, brS) I R (Nujol) cm-': 3320. 172
5. 1675. 15351505, 1270 The following compounds were obtained in the same manner as in Reference Example 32.

Reference Example 36 Melting point 150-151'0 (yield 78%)'HNMR (
90MHz, CDCRs) δ: 0.87 (3H, t)
.

1.50-1.90 (2H, +c), 2.10 (2H
, t), 3.67 (3H, s) 4.83 (2H, q)
, 7.17 7.80 (9H, m), 7.93 8
．． 17(2H,m)IR(Nujol)cm-': 2220. 174
0. 1670. 15301445, 1430.13
90.1345.1290.1280.1250°11
25,770 Reference Example 37 Melting point 85-86°C (yield 75%) 'HNMR (90MHz, CDCQ3) δ: 0.83
(3H, t).

1.07-1.37 (4H, m), 1.50-1.
83 (2H, m), 2.10 (2H, t), 3.
67 (3H, s), 4.83 (2H, q), 7.1
7-7.80 (9H, m), 7.93-8.17 (2
H,m)IR(Nujol)cm-': 2220.
1735.1670. 15301480, 1445
．． 1430. 1390. 1375.1345. 1
290°1270, 1260. 1200. 113
0.775 The following compound was obtained in the same manner as in Reference Example 33.

Reference Example 38 Melting point 130-131"C (yield 78%)'HNMR (
90MHz, CD CQs) a: 1.07 (3H,
L).

1.93 (2H, br s), 2.90 (2H, br s)
s), 3.70(3H,5)5J3(2H,br
s), 6.93-8.07(IIH,m)IR(N
uiol)cm-': 2220. 1710. 14
50. 14001290, 1270.1265.12
00.1125.760 Reference Example 39 Melting point 109-110°C (yield 75%)'HNMR (
90MHz, CDCL) δ: 0.90 (3H, t).

1.17-2.10 (6H, m), 2.90 (2Ht
), 3.70 (3H, s) 5.83 (2H, s),
6.97 (2H, d), 7.13-8.00 (9H,
m)IR(Nujol)cm-': 2220.17
10.1450.1430°1280, 1260.
1190. 1120.750 Reference Example 40 Methyl 3-nitro-4-valerylaminobenzoate Fuming nitric acid (1.4m) was mixed with acetic anhydride (12m+2) under water cooling.
After adding dropwise to the solution, concentrated sulfuric acid (0,1+aQ) was added. While stirring the mixture under water cooling, methyl 4-valeryl aminobenzoate (2.3 g) was added, and the mixture was stirred for 1 hour. The crystals precipitated by adding ice water were recrystallized from ethyl acetate-hexane to give yellow prism crystals (2.14 g, 76%
) was obtained.

Melting point 106-107℃ Elemental analysis value Cr s Hls N z Os as C
(%) H (%) N (%) Calculated value: 55.71; 5.75;
9.99 Actual value: 55.84: 5.80
; 10.01'HNMR (CDCL) J:
0.98 (3H, t), 1.20-1.60 (2H,
m), 1.70 1.85 (2H, +a), 2.5
3 (2H, t).

3.96 (3H, s), 8.28 (IH, dd),
8.91 (IH, d), 8.96 (IH, d), ,
1O-60 (IH, br s) Reference Example 41 Zeta. Water was added to the reaction solution, extracted with ethyl acetate, and the organic layer was washed with water. The solution was dried and concentrated, and the resulting silica was purified by silica gel column chromatography to obtain yellow wrap (3.5 g, quantitative).

'HNMR (200MHz, CD C123) δ: 0
．． 83 (3H, t) 1.15-1.33 (2H, m),
1.55-1.70 (2H, m), 1.992.0
8 (2H, +a), 3.98 (3H, s), 4
．． 27 (lFI, d), 5.55 (IH, d),
7.07 (IH, d), 7.27 (2H, d), 7
．． 42-7.56 (4Hm), 7.62-7.70 (
IH, m), 7.77 (1B, d), 8.19 (I
H, q), 8.61 (IH, d) I R (Neat) cm-': 2220.1730.
1610.1535.1480°1435, 1390.
1345.1285. 1240.765 Reference Example 42 Methyl 4-valerylamino-3-nitrobenzoate (2.1 g), 4-(2-cyanophenyl)benzyl bromide (2.0 g) and K1C05 (1°1 g) in DMF (201112) Methyl 4-[N-(2'-cyanobiphenyl-4-yl)methyl-N-valerylamino]-3-nitrobenzoate (3.5 g) was stirred at room temperature for 4 hours in concentrated hydrochloric acid (4.0 m ) and methanol (
lod), add iron powder (1.3g) while stirring.
) was added little by little.

After stirring at 70-80°C for 1 hour, insoluble materials were filtered off and the filtrate was concentrated. The residue was dissolved in ethyl acetate, washed with water, dried, and concentrated to dryness. The obtained silica was purified by silica gel column chromatography to obtain the desired product as a yellow silica (1.7 g, 53%).

'HNMR (200 MI (z, CDC12x) δ: 0
．． 94 (3H.

t), 1.45 (2H, se), 1.79-1.9
4 (2H, m), 2.89 (2H.

t), 3.94 (3H, s), 5.44 (2H, s
), 7.15 (2H, d).

7.27 (LH, d), 7.42-7.54 (4H,
m), 7.65 (IH, dt).

7.77 (IH, dd), 7.97 (IH, dd),
8.50 (IH, dd) I R (neat) cm”:
2220.1720.1615.1480.1440
゜1400, 1335.1300.1280.1210
．． 755 Reference Example 43 Methyl 4-[N-(2'-cyanobiphenyl-4-yl)methyl-N-valerylamino]-3-nitrobenzoate (1,7 g), sodium azide (3,9 g) and ammonium chloride ( 3.2g) in DMF (17gm
) and stirred at 115°C for 5 days. Water was added to the reaction solution, neutralized with IN-hydrochloric acid, and then extracted with ethyl acetate. The organic layer was washed with water, dried, concentrated to dryness, and the resulting residue was purified by silica gel column chromatography.

The obtained crude crystals were recrystallized from ethyl acetate to obtain colorless needle crystals (0.67 g, 34%).

Melting point 134-136℃ Elemental analysis value C! 7HzmNso f' 1/2H
! C as O (%) H (%) N (%) Calculated value: 68.19; 5.72;
17.67 Actual value: 68.46, 5.7
7; 17.31'HNMR (200MHz, C
DCQs) a: 0.83 (3H, t).

1.18-1.37 (2Lm), 1.50-1.65
(2H, m), 2.38 (2H, t), 3.90 (
3H,s), 5.24(2H,s), 6.68(2
H, d).

6.91 (2H, d), 7.06 (IH, d), 7
．． 28-7.33 (l) I, m) 7.54-7.69 (
3H, m), 7.87 (LH, dd), 8.00 (
IH,ad)TR(KBr)cm-': 1720.
1615.1515. 1435.14101340
1300. 1280. 1220. 1085.7
70.750 Reference Example 44 Methyl 2-butyl-1-[[2'-(I H-tetrazol-5-yl)biphenyl-4-ylcomethyl 1benzimidazole-5-carboxilade (0.3 g)
was heated under reflux for 2 hours in methanol (5-) containing a 2N aqueous solution of caustic soda (lIII2).

The reaction solution was concentrated to dryness and the resulting residue was dissolved in water.

The precipitated crystals were acidified with 1N hydrochloric acid and recrystallized from acetonitrile-methanol to give colorless crystals (0.23g).
, 83%).

Melting point 180-182℃ Elemental analysis value C**C as HxaNsO□ (%)
H (%) N (%) Calculated value: 68.16; 5.49; 1
9.08 Actual value: 68.43; 5.27
; 18.88'H-NMR (200MHz, D
MS○-da) δ: 0.88 (3H, t), 1.
28-1.46 (2H, m), 1.63-1.78
(2H, m) 2.89 (2H, t), 5.58 (2H
, sl 7.07 (4H, s), 7.477.7
0 (5H, m), 7.86 (IH, dd), 8.1
8(IH,s) Reference Example 45 Methyl 3-valerylaminobenzoate methyl 3-
Aminobenzoate (6.0 g) and triethylamine (
Valeryl chloride (4.8 g) was added dropwise to a solution of valeryl chloride (4.5 g) in methylene chloride (90 mI2) while stirring under water cooling, and the mixture was stirred for 1 hour. The reaction solution was washed with hydrogenated sodium hydroxide solution, diluted hydrochloric acid, and water, dried, and then concentrated to dryness. The residue was recrystallized from ethyl acetate-hexane to obtain colorless prism crystals (8.1 g, 87%).

Melting point 101-102℃ 'HNMR (90MHz, CD CQs) δ: 0.9
3 (3H, t).

1.2-1.9 (4H, m), 2.37 (2H, t)
, 3.90 (3H, s), 7°36 (IH, t),
7-51 (IH, br s), 7.70 7-95
(2H, m) 8.03 (IH, t) Reference example 46 )-1-l 4-nitro 3-valerylaminobenzoate methyl 3-valerylaminobenzoate (2°3g)
While stirring the acetic anhydride (12+a12) solution under water cooling, fuming nitric acid (1,4 tQ) was added dropwise, then one drop of concentrated sulfuric acid was added and the mixture was stirred for 2 hours. After adding ice water to the reaction solution and extracting with ethyl acetate, the organic layer was washed with hydrogenated sodium chloride solution and water, and then dried. The solvent was distilled off, and the residue was purified by silica gel column chromatography to give a brown oil (1.0 g, 36
%) was obtained.

'HNMR (90MHz, CDC(ls)δ: 0.9
6 (3H, t) 1.11.9 (4H, m), 2.51
(2H,t), 3-96(3H,s), 7゜80(
lH, dd), 8.26 (lH, d), 9.41 (
1)1. d), 10.23 (IH, br s) I R (neat) cm-': 3380.1730.
1615.1590.15351500, 1440.1
420.1325.1310.1280.1250゜1
210, 1160.1110.1070.845.77
5.740 Reference Example 47 Methyl 3-[N-(2'-cyanobiphenyl-4-yl)methyl-N-valerylamino]-4-dimethyl 4
-Nitro-3-valerylaminobenzoate (1,0g
), 4-(2-cyanophenyl)benzyl bromide (0
, 97 g) and potassium carbonate (0.55 g) in DMF
The mixture was stirred for 2 days at room temperature in (l Oim). After adding water to the reaction solution and extracting with ethyl acetate, the organic layer was washed with water and dried. The solvent was distilled off, and the resulting residue was purified by column chromatography to obtain a pale yellow oil (1,
24g (73%) was obtained.

'HNMR (200MHzCDC12x) δ: 0.8
4 (3H, t) 1.17-1.30 (2H, m), 1
．． 56-1.71 (2H, m), 1.802.08 (
2H, m), 3.92 (3H, s), 4.43 (L
H,d), 5.37(11(,d), 7.26(2
8, d), 7.40-7.51 (4H, m), ? ,
607.69 (2H, m), 7.75 (LH, d),
7.97 (IH, d), 8.16 (IH, dd) I R (neat) cm-': 2220.1735.
1675.1600.15801530 1480, 1
435.1420.1390.1350.128512
20, 1200.1115.1090.825.775
．． 765 Reference Example 48 Methyl 3-[N-(2'-cyanobiphenyl-4-yl)methyl-N-valerylamino]-4-nitrobenzoar) (1,2 g) was dissolved in methanol (1,3d) containing concentrated hydrochloric acid (1,3d). After adding iron powder (0.45g) little by little while stirring at room temperature,
The mixture was stirred at ℃ for 3 hours. After water and ethyl acetate were added to the reaction mixture, the mixture was made alkaline with sodium hydrogen aqueous solution. The deposited precipitate was filtered off, and the organic layer separated from the filtrate was washed with water and dried. The residue obtained by distilling off the solvent was purified by silica gel column chromatography. The obtained crude crystals were recrystallized from ethyl acetate to give colorless needle crystals (0.5 g, 45%).
I got it.

Melting point: 166-167℃ Elemental analysis value: C (%) as C2AH2%N201
H (%) N (%) Calculated value: 76.57; 5.95; 9.
92 actual value: 76-39 i 6.05,
9.79'HNMR (200MHz, CDCQs) δ:
0.94 (3H, t).

1.35-1.54 (2H, m), 1.79-1.9
4 (2H, m), 2.88 (2B, t), 3.92
(3H,s), 5-47(2H,s), 7.14(
2H, d).

7.40-7.53 (4H, n+), 7.60-7.
68 (IH, m), 7.74-7.80 (2H, m)
, 7.96-8.02(2H,+a)IR(KBr
)c-': 2210.1715.162θ, 1
580.1510°1480, 1460.1425.1
410.1340.1325.1280°1270, 1
250.1230.1185.1105.1080.7
70°760,745 Reference Example 49 Methyl 2-butyl-1-[2'-(cyanobiphenyl-4-yl)methyl 1benzimidazole-6-carpoxylate (0.5 g), sodium azide and ammonium chloride (1, Add 15g) to DMF (5d),
Stirred at 115°C for 3.5 days.

Water was added to the reaction solution, acidified with IN-hydrochloric acid, and then extracted with ethyl acetate. The organic layer was washed with water, dried, and concentrated to dryness, and the resulting residue was purified by silica gel column chromatography. The obtained crude crystals were recrystallized from ethyl acetate-methanol to obtain colorless crystals (0.23 g, 41%).

Melting point 224-225℃ Elemental analysis value C (%) as C,, H□N, O,
H (%) N (%) Calculated value: 6g, 98, 5.66;
17.88 Actual value: 68.89; 5.6
8; 17.66'H-NMR (200MHz,
DMSO-dsM: 0.87 (3)1. t),
1.26-1.45 (2H, m), 1.63-1-
78 (2H, +m).

2.85 (2H, t), 3.85 (3H, s), 5
．． 62 (21, s), 7.00 (2B, d), 7.
07 (2H, d), 7.48-7.70 (5) 1. m
), 7.82 (IH, dd), 8.14 (IH, S
)IR(KBr)cm-': 1725.1460.
1450.1435.1340°1265, 1235.
775.760.745 Reference Example 50 5-yl)biphenyl-4-yl 1methyl 1benmethyl 2-butyl-1-[[2'-(IH-tetrazole-
5-yl)biphenyl-4-yl 1methyl 1benzimidazole-6-carpoxylate (0.1 g) in
Methanol containing caustic soda aqueous solution (0,-5-) (
51111) for 5 hours under reflux. Distill the solvent,
IN-hydrochloric acid (0,5-) was added to the residue, and the mixture was extracted with chloroform. The organic layer was washed with water, dried, and concentrated to dryness. The resulting crude crystals were recrystallized from methanol-ethyl acetate to yield colorless crystals (60 mg).

58%).

Melting point 258-259℃ (decomposition) Elemental analysis value CxsH*aN 10! ” l/2E
to Act C (%) H (%) N (%) Calculated value: 67.73; 5.68;
16.92 Actual value: 67.79; 5.50
, 16.89'HNMR (200MHz, DMSO
dsM: 0.87 (3H, t), 1.27-1.4
5 (21, m), 1.63 1.79 (2H, w).

2.85 (2H, t), 5.60 (2H, s), 7
．． 00 (2H, d), 7.08 (2H, d), 7.
48 (5H, m), 7.84 (lH, dd), 8.1
1(II(,s)IR(KBr)co+-': 17
30.1460.1410.1335.1285126
5, 1225.780.760 Reference Example 51 Methyl 2-amino-5-methylbenzoate Concentrate 2-amino-5-methylbenzoic acid (10 g)! 11 (5,5
ill12) in t-containing methanol (50I112),
The mixture was heated under reflux for 19 hours. The solvent was distilled off, and the residue was dissolved in water, neutralized with an aqueous solution of caustic soda, and extracted with ethyl acetate. The organic layer was dried and concentrated to give a light brown oil (8.1g
, 74%).

'H-NMR (90 MHz, CDCl23) δ: 2.
24 (3H, s).

3.89 (3H, s), 5.55 (2B, s), 6
．． 59 (IH, d), 7.10 (11, dd), 7
．． 68 (LH, d) Reference example 52 Methyl 5-methyl-2-valerylaminobenzoate methyl 2-amino-5-methylbenzoate (8,1
g) and triethylamine (6.0 g) in methylene chloride (
50j2) While stirring the solution under water cooling, valeryl chloride (6.5 g) was added dropwise. After reacting for 2 hours, the reaction solution was washed with an aqueous sodium carbonate solution, diluted hydrochloric acid, and water in that order.
Dry. The solvent was distilled off to give a pale brown oil (12.8 g,
99%).

'H-NMR (90MH2, CDCl23) δ: 0.
95 (3H, t) 1.2 1.9 (4H, m), 2.
33 (3H, s), 2.43 (2) (, t), 3゜93 (3H, s), 7.34 (IH, dd), 7.
82 (LH, d), 8.62 (IH.

d) Reference Example 53 After adding fuming nitric acid (6.7 m) dropwise to a mixture of methyl 5-methyl-2-valeryl aminobenzoate (12.8 g) and acetic anhydride (5.9 g) while stirring under water cooling, The mixture was stirred and left for 3 hours. Ice water was added to the reaction solution, extracted with ethyl acetate, washed with hydrogenated sodium chloride solution and water, dried, and the solvent was distilled off. After the residue was purified by silica gel column chromatography, the obtained crystals were recrystallized from isopropyl ether to obtain colorless crystals (8.5 g, 60%).

Melting point 59-60°C 'HNMR (200MHz, CDCL) δ: 0.94
(3H, t).

1.31-1.50 (2H, m), 1.63-1.7
8 (2H, m), 2.43 (2H, t), 3-95
(3H,s), 7.90(lH,d), 8.00(
LH, d).

10.16 (LH, s) Reference Example 54 Melting point 141-142°C 'H-NMR (200MHz, CD CQs) δ: 0
．． 85 (3n, t) 1.17-1.36 (2H, m),
1.60-1.75 (2H, m), 2,052.1
5 (2H, m), 2.49 (3H, s), 3.64
(3H, s), 4.62 (tH, d:+, 4.94
(LH, d), 7.21 (2Hd), 7.38-7
．． 50 (4H, m), 7.59 7.68 (IH, m
), 7.73-7.77 (3H, m).

7.89 (IH, m) Reference Example 55 Methyl 5-methyl-3-nitro 2-valeryl aminobenzoate (5,89 g), 4-(2-cyanophenyl)benzyl bromide (5,44 g) and Potassium carbonate (3.0 g) was stirred in DMF (50 m) at 50° C. for 15 hours. Water was added to the reaction solution, extracted with ethyl acetate, and the organic layer was dried. The solvent was distilled off, and the residue was purified by silica gel column chromatography. The obtained crystals were recrystallized from ethyl acetate-hexane to give colorless crystals (
3.1g.

32%).

Meq-2-[[N-(2'-cyanobiphenyl4-yl)methyl-N-valeryl]amino]-5-methyl-3
-Nitrobenzoate (3.1 g) in concentrated hydrochloric acid (4.4 d)
) and methanol (22J2), add iron powder (1.6 g) little by little while stirring, and then
The mixture was heated to reflux for an hour. After removing insoluble matter by filtration, the filtrate was concentrated, water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with sodium hydrogen aqueous solution and water, dried, and then the solvent was distilled off. The residue was purified by silica gel column chromatography to obtain a pale brown oil (2.8 g, quantitative).

'H-NMR (200MHz, CDCl2.) δ: 0
．． 95 (3H, t).

1.37-1.56 (2H, m), 1.79-1.9
4 (2H, m), 2.47 (3H, s), 2.90
(2H, t), 3.71 (3H, s), 5.79 (
2H,s).

6.96 (2H, d), 7.39-7.46 (5B,
m), 7.58-7.66 (IH, m), 7.73
7.77(2H,m)IR(neat)cm-':
2220.1720.1520.1480.1435
゜1410, 1305.1245.1215.1195
．． 1110.1040780, 760 Reference-Example 56 Ethyl 2-amino-6-methylbenzoate Reference Example 5
It was synthesized according to 1.

Melting point Oil (yield 82%) 'HNMR (90 MHz, CDC(is) J: 1.
34 (3H, t).

2.43 (3H, s), 4.35 (2H, q), 5
．． 06 (2H, br s), 6.50 (2H, d),
7.07 (IH, t) Reference Example 57 Ethyl 6-methyl-2-valerylaminobenzoate Synthesized according to Reference Example 52.

Melting point 56-57℃ (yield 70%) 'H-NMR (90MHz, CDC(Is) δ: 0
．． 93 (3H, t).

1.39 (3H, t), 1.18-1.87 (4H,
+o), 2.37 (2H, t) 2.46 (3H, s)
, 4.41 (2H, q), 6.94 (IH, d),
8.27 (IH, d), 7-32 (IH, t),
9.69 (IH, br s) Reference Example 58 Synthesized according to Reference Example 53.

Melting point 103-104℃ (yield 52%)” HNMR (9
0MHz, CDCl25) δ: 0.93 (3H, t)
.

1.35 (3H, t), 1.17-1.85 (4B,
m), 2.38 (2H, t).

2.49 (3H, s), 4.38 (2H, q), 7
．． 14 (lH, d), 7.97 (IH, d) Reference Example 59 Synthesized according to Reference Example 54.

Melting point Oil (yield 80%) 'H-NMR (200MHz, CDCL) δ: 0.8
6 (3H, t).

1.34(3)1. t), 1.20-1.45 (2H
, m), 1.60-1.78 (2H, m), 2.14
(2H, t), 2.40 (3H, s), 4.09 (
1)(,d).

5.28 (18, d), 4.23-4.42 (2H,
m), 6.81-6.96 (10B, m), 7-1
9-7.53 (13H, m), 7.69 (1) 1. d
), 7°88 (1B, dd) Reference Example 60 Methyl 2-amino-5-chlorobenzoate 2-7mi/-5-benzoic acid 11 (25.5g) (1')) Add sulfuric acid (12m) and
The mixture was heated under reflux for 4 hours. The reaction solution was concentrated and water (30011
After adding I2), it was neutralized with potassium carbonate.

After extraction with ethyl acetate, washing with water and drying, the solvent was distilled off. The obtained crude crystals were recrystallized from i-propyl ether-benzene to give pale yellow crystals (17°Ig.

63%).

Melting point 6B-70°C Reference example 61 Methyl 5-chloro-2-valerylaminobenzoate methyl 2-amino-5-chlorobenzoate (15g
) and triethylamine (12d) in methylene chloride (15
Valeryl chloride (10m) was added dropwise to the solution while stirring under water cooling, and the mixture was further stirred at room temperature for 2 hours. The reaction solution was washed with hydrogenated sodium chloride solution and water, and then dried. The solvent was distilled off to obtain pale yellow crystals (13.4 g, 61%).

Melting point 48-49°C Reference Example 62 Methyl 5-chloro-2-valerylaminobensia)
Fuming nitric acid was added dropwise to a solution of (13.4 g) in acetic anhydride (10 m) while stirring under water cooling. After stirring at room temperature for 1 hour, ice water was added and left to stand. The precipitated crystals were collected by filtration and recrystallized from isopropyl ether to give pale yellow crystals (9,5
g, 61%) was obtained.

Melting point 84-85°C Reference example 63 Methyl 5-chloro-3-nitro-2-valerylaminobenzoate (3.15 g), 4-(2-cyanophenyl)penzylbromi F (2.8 g) and potassium carbonate (1 -8g) was stirred in DMF (50m) at room temperature for 3 hours. The reaction solution was directly concentrated to dryness, the residue was extracted with ethyl acetate, H, and O, and the organic layer was washed with water and dried. The crude crystals obtained by distilling off the solvent were recrystallized from ethyl acetate-benzene to obtain colorless crystals (4.0 g, 79%).

Melting point 137-138°C Reference example 64 Ruaminobenzoate (0.93g) in DMF (l 0
m1) Potassium carbonate (0,5 g) and N-triphenylmethyl-5-[2-(4'-70momethyl)
[biphenylmethyl]tetrasheet b (1.84 g) was added and stirred at room temperature for 19 hours. Water (50 m
12) was added and extracted with ethyl acetate. The organic layer was washed with water, dried, and the solvent was distilled off. The residue (38 g) was purified by silica gel column chromatography to give pale yellow crystals (
1.89 g, 82%) was obtained.

'HNMR (200MHz, CDC45) δ: 0.8
6 (3H, t) 1.17-1.35 (2H, m), 1
．． 56-1.80 (2H, m), 2.032.10 (
2H, m), 3.63 (3H, s), 4.41 (L
H, d), 4.82(l)l, d), 6.76-6
．． 98 (IOH, m), 7.20-7.54 (12)
1m), 7.88 (IH, d), 7.90-7.9
3 (IH, m), 7.98 (IHd) I R (KBr) cm-': 1750.1690.1
555.1295.1270°1225, 760.71
0 Reference Example 65 Methyl 5-ri4-3-ditro-2-valerimidazole-7-carpoquinlatomethyl 5-chloro-2-[N-(2'-cyanobiphenyl-4-yl)methyl-N-valeryl 1 Amino-3-
Nitrobenzoate (3.33 g) concentrated hydrochloric acid (4 m12
) and methanol (50ml), and while stirring at room temperature, iron powder (95% purity, 1.1g) was added little by little, followed by stirring at 80°C for 24 hours. Insoluble materials were removed by filtration, the filtrate was concentrated to dryness, and the residue was extracted with ethyl acetate-water. Soak the organic layer in diluted water.

After washing with water, it was dried and concentrated. The solvent was distilled off and the residue was purified by silica gel chromatography to give colorless needle crystals (1
, 83g, 61%) was obtained.

'HNMR (200MHz, CDC4*) δ: 0.9
6(3H,t)1.38-1.57(2)1. m),
1.80-1.95 (2H, +a), 2.92 (2H
,t), 3.72(3H,s), 5.79(2H,
s), 6.94 (2H, d).

7.41 7.49 (4H, m), 7.59-7.6
3 (1B, m), 7.73-7.78 (IH, m),
7.61 (LH, d), 7.91 (IH, d) Reference Example 66 Ethyl 2-carboxy-3-nitropenzoa 3-nitrophthalic acid (35 g) in ethanol (300 m4) containing concentrated sulfuric acid (20 m12), The mixture was heated under reflux for 24 hours. The solvent was distilled off, the residue was poured into cold water (700 d), and extracted with ethyl acetate. After washing the organic layer with water.

After shaking and separating the mixture from an aqueous potassium carbonate solution, the aqueous layer was made acidic with hydrochloric acid and extracted with methylene chloride. The organic layer was washed with water, dried, and the solvent was distilled off. Obtained solid (29g, 74%
) was used as it was in the next reaction without purification.

'H-NMR (90MHz, CD Cf2s) δ: 1
．． 43 (3H, t) 4.47 (2H, q), 7.70
(IH, t), 8.40 (2H, d), 9.87 (
IH, br s) I R (Nujol) am-': 1725.1535
．． 1350.1300° Reference Example 67 Ethyl 2-carboxy-3-nitrobenzoate (2
3.9g) and thionyl chloride (12g) were heated under reflux in -tobenzene (150il12) for 3 hours.

A solution of acid chloride (26 g, quantitative) obtained by concentration to dryness in methylene chloride (20 m) was added to sodium azide (9,
It was added dropwise to a DMF (2011I2) mixture of 75 g) with vigorous stirring. After the reaction, ether-hexane C3m
: 1.200wM) and water (25011I2) to separate the liquids. The organic layer was washed with water, dried, and the solvent was distilled off. The obtained residue was dissolved in t-butanol (200d), the temperature was gradually raised while stirring, and the mixture was then heated under reflux for 2 hours. The reaction solution was directly concentrated under reduced pressure to obtain an oil (30 g).

'HNMR (90MHz, CDCff5) δ: 1.4
0 (3H, t).

1.53 (9H, s), 4.43 (2H, q), 7
．． 23 (lH, t), 8.03-8.27 (2H, m
), 9.70 (LH, br s) I R (Neat)
cm-': 3320.29B0.1740.1700
．． 1585°1535, 1500.1440.1375
．． 1265.1155 Reference Example 68 Ethyl 2-t-butoxycarbonylamino-3-nitrobenzoate (20 g) was dissolved in THF (50 wi), and while stirring under water cooling, sodium hydride (60% oil, 2.8 g) was added. After addition, 2-cyanobiphenylmethylbromide (18 g) and potassium iodide (0', 36
g) was added and stirred at room temperature for 15 hours. Further, the mixture was heated under reflux for 4 hours. The solvent was distilled off and water (250
wt1) and ether (200m). The organic layer was washed with water, dried, and concentrated to obtain a yellow oil. Trifluoroacetic acid (6(1+42) and methylene chloride (40
m12) and left stirring at room temperature for 1 hour.

The reaction solution was concentrated to dryness, and ethyl ether (2Q O
When n) was added, crystals were precipitated. After filtering, washing with ether and drying, pale yellow crystals (22.1 g, 85%) were obtained.

Melting point 119-120°C 'H-NMR (90MHz, CDCL) δ: 1.37
(3H, t).

4.23 (2H, s), 4.37 (2H, q), 6
．． 37 (IH, t), 7.33-7.83 (9H, m
), 7.97-8.20 (2H, m) I R (Nuj
ol) cm-I: 3280.2220.1690.1
575°1530, 1480.1450.1255.1
125.1105.755 Reference Example 69 Ethyl 2-[(2'-cyanobiphenyl-4-yl)
Methyl 1-amino-3-nitrobenzoate (5.5g)
Raney nickel (5 g) in THF (5072) solution of
was added, and catalytic reduction was carried out at room temperature under normal pressure. The catalyst was filtered off and the filtrate was concentrated to give a yellow oil (5 g, quantitative).

'H-NMR (90MHz, CDCQs-D, O) a:
1.30 (3Lt), 4.23 (2 days, s),
4.27 (2H, q), 6.87-7.03 (2
B, m), 7.33-7.87 (9H, +n) I R
(Neat)cm-': 3435.3350.298
0.2220.1690°1615, 1465.136
5.1280.1240.1215.1190°106
5,755 Reference Example 70 Uniru-4-yl)methyl 1-benzoate (0.31g
) and ethyl butyrimidate (0.18 g) were dissolved in ethanol (2-) and stirred at 70°C for 2 hours. The reaction solution was concentrated to dryness, and the residue was dissolved in ethyl acetate and sodium hydrogen aqueous solution. The organic layer was washed with water, dried, and concentrated, and the resulting crude crystals were recrystallized from ethyl acetate-hexane to give pale yellow needle-like crystals C0.
-22g, 60%) was obtained.

Melting point 112-114℃ 'HNMR (90MHz, CDCff5) δ: 0.9
3 (3H, t).

1.20 (3H, t), 1.33-2.07 (4B,
m), 2.90 (2H, t).

4.20 (2H, q), 5.87 (2H, s), 7
．． 00 (2H, d), 7.17-8.03 (9H, +
o) I R(Nujol)c+m-': 2220.172
5.1480.1450°1420, 1400.128
5.1255.1245.1190.1110° Reference Example 71 Ethyl 3-amino-2-[(2'-cyanobifimidazolemethyl 2-butyl-1-[(2'-cyanobiphenyl-4-yl)methyl]pen) While heating a solution of zimitasol 7-carpoxylate (10 g) and NaB H+ (2.2 g) in tetrahydrofuran (100 wj2) under reflux, methanol (19t12) was added dropwise in small portions over about 80 minutes.The mixture was further heated under reflux for 27 hours. Thereafter, the reaction solution was concentrated to dryness, water was added to the residue, and the mixture was neutralized with concentrated hydrochloric acid. The precipitated crystals were collected by filtration and recrystallized from methanol to yield colorless needle crystals (8.8 g).

93%).

Melting point 203-204℃ Elemental analysis value C□Hx s N s C as O (%)
H (%) N (%) Calculated value: 78.96, 6.37;
10.62 Actual value: 79.24; 6.3
6 i 10.69NMR (200MHz,
CD CL) δ: 0.94 (3) 1. t), 1.
36-1.55 (2H, m), 1.79-1.95 (
2H, m), 2.85 (2H.

t), 4.66 (2H, d), 5. ．． 82 (2H,
s), 7.04 (2H, d), 7゜10 (IH, d
d), 7.18-7.26 (IH, m), 7.40
-7.52 (4H.

m), 7.64 (IH, dt) TR (KBr) cm-': 3200.2210.
1510. 1480.14551425, 1410
．． 1280. 1,015.765.750 Reference Example 7
2 Dazole 2-butyl-1-[(2'-cyanobiphenyl4-yl)methyl 1-7-hydroxybenzimidazole (5,
A catalytic amount of DMF (1 drop) was added to a chloroform solution (8011I2) of 4 g) and thionyl chloride (8.3 g),
The mixture was heated to reflux for an hour. The reaction solution was washed with sodium hydrogen aqueous solution and water, dried, and then concentrated to dryness. The resulting residue was recrystallized from ethyl acetate-hexane to give colorless needles (5.3 g, 92%).
I got it.

Melting point 144-145℃ Elemental analysis value C (%) as H□CffN
H (%) N (%) Calculated value: 75.44; 5.84,
10.15 Actual value: 75.29, 5.87
, 10.04NMR (200MHz, CDCl2
．． ) δ: 0.96 (3H, t), 1.38-1.5
7 (2H, m), 1.82-1.97 (2H, m),
2.88 (2H.

t), 4.60 (2H, s), 5.78 (2H, s
), 7.07 (2H, d), 7゜14 (LH, dd
), 7.21(lH,d), 7.41-7.54(
4H, m), 7°60-7.69 (IH, m), 7
．． 75-7.84 (2H, m) I R (KBr) cm”
: 2210.1515.1480.1450.142
5°1400, 1350.1280.760.745.
690 Reference Example 73 Dazole 2-butyl-1-[(2'-cyanobiphenyl-4-yl)methyl]-7-chloromethylbenzimidazole (
0.83g) and sodium cyanide (0°12g)
The mixture was stirred for 22 hours using a MF (10 m) medium source. Water was added to the reaction solution, extracted with ethyl acetate, and the organic layer was washed with water and dried. The residue obtained by distilling off the solvent was crystallized from ethyl acetate to obtain colorless prism crystals (0.76 g, 94%).

Melting point 180-181'C! Elemental analysis value CzyHz4N, C (%) H (%) N (%) Calculated value:
80.17; 5.98; 13.85 Actual value: 80.22; 6.17;
13.69 Reference Example 74 2-Butyl-1-[(2'-cyanobiphenyl4-yl)methylco-7-cyanomethylbenzimidazole (0
, 76g) in ethanol (Ion) containing 3.5N-hydrochloric acid.
) and heated under reflux for 2.5 hours.

The reaction solution was diluted with water, made alkaline by adding sodium bicarbonate solution, extracted with ethyl acetate, and the organic layer was washed with water.

Dry. The residue obtained by distilling off the solvent was purified by silica gel column chromatography to obtain a colorless oil (0.9
g, quantitative) was obtained.

NMR (200MHz, CD C12,) δ:
0.94 (3Fl, t), 1.23 (3Ht),
1.37-1.55 (2FI, m), 1.8O-1-
95 (2H, m).

2.85 (2H, t), 3.65 (2H, s), 4
．． 10 (2H, q), 5.73 (2H, s), 7.
01-7.07 (3B, m), 7.21 (IH, t)
, 7.74-7.68 (5H, m), 7.71-7
．． 78(2H,m)IR(neat)cm-': 2
210.1730.1510.1475.1435゜1
400, 1365.1350.1275.1040.
760. 735 Reference Example 75 2-Butyl-1-[(2'-cyanobiphenyl-4-yl)methyl]-7-chloromethylbenzimidazole (
0,,62g), tributyltin hydride (3°0g-)
and perbenzoic acid (catalytic amount) in toluene (20−),
The mixture was heated under reflux for 5.5 hours under a nitrogen stream. The reaction solution was concentrated, purified by silica gel column chromatography, and recrystallized from ethyl acetate-hexane to give colorless crystals (0.5 g, 88
%) was obtained.

Melting point 115-116℃ Elemental analysis value C (%) H (%) N (%) Calculated value: 82.29; 6.64; 11
．． 07 actual value: 82.30; 6.74
; 10.94NMR (200MHz, C
D CQs) δ: 0.93 (3B, t) 1.35-1
．． 53 (2H, m), 1.77-1.92 (2H,
m), 2.51 (3H, s), 2.82 (2H, t
), 5.64 (2H, s), 6.94 (IH, d)
.

7.05 (2H, d), 7.15 (IH, t), 7
．． 41-7.53 (4H, m).

7.60-7.68(2)1. m), 7.76 (IH
, d) IR(KBr)cm-': 2210. 15
95. 1515. 1480.1460°1415,
1400. 1345.1280. 780. 76
0. 740 Reference Example 76 Zole 2-butyl-1-[(2'-cyanobiphenyl-4-yl)methyl]-7-medoxybenzimidazole (1,
2 g) of methylene chloride (5-) under a nitrogen stream.
Boron tribromide (1.7 g) was added at 2°C. After stirring at room temperature for 8 hours, water was added and stirring was further continued for 1 hour. The reaction solution was made alkaline with 6N caustic soda water, and then extracted with ethyl acetate. The organic layer was washed with water, dried, and concentrated, and the resulting residue was purified by silica gel column chromatography. The obtained crude crystals were recrystallized from ethyl acetate-hexane to obtain colorless prism crystals (0.69.63%).

Melting point 185-186℃ Elemental analysis value CzsHzsC as NsO (%)
H (%) N (%) Calculated value: 7B, 71; 6.08;
11.02 Actual value: 78.70 i6.
07;11.01'H-NMR (200MHz, CD
Cl23M: 0.81 (3H, t).

1.22-1.42 (2H, +m), 1.66-1.
81 (2H, m), 2.80 (2H, t), 5.8
1 (2H, s), 6-71 (IH, d), 7.00
(IH, t).

7.19-7.26 (3H, m), 7.38-7.5
0 (4H, m), 7.61 (IH, m), 7.74
(4H, d) I R(KBr) cm-': 2210.1615.1
590.1500.1475゜1440, 1410.1
365.1290.1195.1160.1065゜7
80, 755.725 Reference Example 77 2-Methoxy-6-nitroaniline 2-amino-3-nitrophenol (7.7 g) and potassium carbonate (7.6 g) were mixed in DMF (15 m) at room temperature for 3
After stirring for 0 minutes, methyl iodide (7.8 g) was added, and the mixture was further stirred at room temperature for 5 hours.

Water was added to the reaction solution, extracted with ethyl acetate, and the organic layer was washed with water and dried. The crude crystals obtained by distilling off the solvent were recrystallized from isopropyl ether to give orange prism crystals (6
, 9g, 82%) was obtained.

Melting point: 7°C - 77°C Reference Example 78 N-(2-methoxy-6-nitrophenyl)valeramide A catalytic amount of concentrated sulfuric acid was added to a mixture of 2-methoxy-6-nitroaniline (5.9 g) and valeric anhydride (14 g). Add 1
Stir at 30-140°C for 1.5 hours. Water was added to the reaction solution, and the mixture was made alkaline with 6N-caustic soda water. The reaction solution was extracted with ethyl acetate, and the organic layer was washed with water and dried. The solvent was distilled off, and the residue was purified by silica gel column chromatography. The obtained crude crystals were recrystallized from ethyl acetate-hexane to obtain colorless crystals (3.2 g, 36%).

Melting point 113-114℃ HNMR (90MHz, CD C12,) δ:
0.95(31(,L).

1.33-1.51 (2H, m), 1,641.79
(2H, m), 2.42 (2Ht), 3.94 (3
1(,s), 7.14(1)1. dd), 7.26
(1)1. t)7.51. (II, dd), 7.64
(LH,br s)I R(KBr)am"": 33
00.1670.1600.1590.1545152
0, 1485.1460.1430.1360.127
5.1055°Reference Example 79) was obtained.

H-NMR (90MHz, CD CQJ &
: 0.84 (3H, t).

1.12-1.35 (2H, m), 1.56-1.7
0(21(,m), 1,912.23(2H,m),
3.61 (3H, s), 4.42 (18, d),
5.20 (IH, d), 7.03-7.12 (IH,
m), 7.22 (2H, d), 7.347.49 (
6H,m), 7.63(l)l,m), 7.74(
LH, d) I R (Neat) cm-': 2220.
1670.1535.1480.1390°1275,
1050.800.760.730 Reference Example 80 A solution of leloamide N-(2-methoxy-6-nitrophenyl)(leloamide (3.2 g) in DMF (15 m) was mixed with sodium hydride (60% oily, .61 g) and
After stirring for 20 minutes, 4-(2-cyanophenyl)benzyl bromide (3.5 g) was added and stirred at room temperature for 1 hour. Water was added to the reaction solution, extracted with ethyl acetate, and then the organic layer was washed with water and dried.

The solvent was distilled off, and the residue was purified by silica gel column chromatography to give a yellow oil (5.8 g, quantified amount of N-[(2'-cyanobiphenyl-4-yl)methyl).
-N-(2-methoxy-6-nitrophenyl)valeramide (5.8 g) and methanol (50 m) of salt preparation a (7 m)
m) Iron powder (23 g) was added little by little while stirring the solution at room temperature. After the reaction mixture was heated under reflux for 5 hours, the solvent was distilled off, and ethyl acetate and water were added to the residue obtained. 6
After making the mixture alkaline with N-caustic soda water, insoluble matters were removed by filtration and the filtrate was separated into liquids. After washing the organic layer with water and drying, the solvent was distilled off, and the resulting residue was recrystallized from ethyl acetate-hexane to obtain colorless prism crystals (4.1 g, 80%).

Melting point 127-128°C H-NMR (200MHz, CDCl2.) δ: 0.
91 (3H, t).

1.32-1.51 (2Lm), 1.73-1.89
(2H, m), 2.79 (2H, t), 3.83 (
3H,s), 5.71(2H,s), 6.69(I
H, d) 7.11 7-19 (3H, m), 7.38
-7.51 (5H, m), 7.63 (IH, m),
7.76(IH,d) I R(KBr)am-': 2210.1605.1
585.1505.1480゜1460, 1445.1
420.1400.1280.1255.1090゜7
70, 720 Reference Example 81 Midazole 2-butyl-1-[(2'-cyanobiphenyl-4-yl)methyl]-7-hydroxymethylpenzimidazole (0.79 g), thionyl chloride (0.36 g) and DMF (catalytic amount) in chloroform (20III2),
The mixture was heated under reflux for 1 hour. The solvent was distilled off, the residue was dissolved in methanol (15m), and sodium methoxide (4,9
M methanol solution, 2-) was added, and the mixture was heated under reflux for 6 hours. The solvent was distilled off, water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried, and the solvent was distilled off. The resulting residue was purified by silica gel column chromatography to obtain an oil (0.48 g, 59%).

'HNMR (90MHz, CDCQs) δ: 0.92
(3H, t).

1.20-2.05 (4H, m) 2.84 (2H,
t), 3.30 (3H, s).

4.34 (2H, s), 5.74 (2H, s), 6
．． 90-7.90(11H,m)IR(neat)a
m-1: 2220.1520.14g0.1460.
14401425, 1280.1190.760 The following compounds were obtained in the same manner as in Reference Example 32.

Reference Example 82 Melting point Oil 'HNMR (90MHz, CDC12x) δ: 1.3
0 (3H, t) 1.97 (3H, s), 4.17 (2
)1. q), 4.73 (IH, d), 4.83 (I
H, d), 7.17-8.17 (IIH, m) I R
(Neat)cm-': 2985.2230.173
0.1675.16001540, 1390.1365
．． 1285.770 Reference Example 83 Melting point Oil 'H-NMR(90MHz, CDC(l
s) δ: 1.13 (3H, t).

1.27 (3H, t), 2.17 (2H, q), 4
．． 13 (2H, q), 4.77 (LH, d), 4.
83 (IH, d), 7.10-8.17 (IIH, m
)IR(Neat)am-': 29B5.2220
．． 1?30.1675.1600゜1535, 14B0
．． 1445.1390.1350.1290.1265
゜1210, 770 Reference Example 84 Melting point Oil 'HNMR (90MHz, CDC (+3) δ: 1.0
7 (3H, d).

1.13 (3H, d), 1.30 (3H, t), 2
．． 03 2.47 (IH, m) 4.20 (2! (, q)
, 4.70 (IH, d), 5.13 (IN, d),
7.17-8-27 (IIH, m) I R (Neat) cm-': 2980.2220.
1730.1670.15901530, 1480.1
390. 1350. 1285.1260. 124
0°1205,765 The following compound was synthesized in the same manner as in Reference Example 33.

Reference Example 85 Melting point 167-168°C (yield 81%)'HNMR (9
0MHz, CDCl25) δ: 1.20 (3H, t)
.

2.63 (3 days, s), 4.20 (2H, q),
5.83 (2H, s), 7.00 (2H, d),
7.17 7.97 (9B, m) I R (Neat)
cm-': 2220.1705.1395.1280
．． 1265゜2IO Reference Example 86 Ethyl 1-t(2'-cyanobiphenyl-4-128
0, 1250, 1205, 1140, 1110, 765
, 740 Reference Example 88 Melting point 163-164°C (yield 76%)'HNMR (9
0MHz, CDCQs) a: 1.20 (3H, t).

1.47 (3H, t), 2.93 (2H, q), 4
-20 (2H, q), 5.83 (2H, s), 6.
97 (2H, d), 7.17-8.00 (9H, m)
IR(Nujol)cm-': 2220.1720
．． 1480.1450°1420, 1400.1380
．． 1280.1250.1200.1145° Reference example 8
7 Melting point 107-108°C (yield 77%)'HNMR (9
0MHz, CDCQsM: 1.17 (3H,L).

1.43 (6H, d), 3. O3-3-47CIH,
+), 4.17 (2H, q).

5.87 (2H, s), 6.93 (2H, d), 7
．． 17-7.80 (8H, +m).

7.97 (11 (, d) I R (Nujol) cm-': 2220.1?30
．． 1440.1400゜ethyl 3-amino-2-[(
2'-cyanobiphenyl-4-yl)methyl]aminobenzoate (1,0 g) and triethylamine (0,3 g
) Chloroacetyl chloride (0-24 ml) was added little by little to a methylene chloride solution (loml) of the above solution under water cooling. The mixture was stirred for 13 hours and then concentrated, and the resulting residue was washed with water and dried. After dissolving in ethanol (10 ml), concentrated hydrochloric acid (1 ml) was added, and the mixture was heated under reflux for 6 hours. The residue obtained by concentrating the reaction solution was dissolved in methylene chloride and water, and the solution was made alkaline with 1N-NaOH. The crude crystals obtained by adding water to the organic layer, drying and concentrating were recrystallized from ethyl acetate-isopropyl ether to obtain colorless crystals (0.88 g, 76%).

'HNMR (200MHz, CDCQs) δ: 1.2
1 (3H, t).

4.21 (2H, q), 4.83 (2H, s),
6.02 (2H, s), 7.02 (2H, d),
7.29-7.49(5)1. m), 7.58-7
．． 79 (3H, m).

8.00 (IH, dd) Reference Example 89 7.99 (LH, dd) The following compound (Reference Example 9O-93
) was obtained.

Reference Example 90 Ethyl 2-chloromethyl-1-[(2'-cyanobiphenyl-4-yl)methyl]benzimidazole-7-
Carpoxylate (0,8g) and 28% NaOMe
(1,08g) solution (methanol) in methanol (15g)
ml) and heated under reflux for 2 hours. The residue obtained by concentrating the reaction solution was dissolved in CHICI 2 HzO, and the organic layer was washed with water and dried.

The syrup obtained by concentration was purified by silica gel column chromatography to obtain yellow syrup (0°4 g, 52
%) was obtained.

'HNMR (200MHz, CDC45) δ: 3.4
3 (3H, s).

3.72 (3H, s), 4.78 (2H, s), 5
．． 97 (2H, s), 6.99 (2H, d), 7.
25-7.49 (5H, m), 7.55-7.77 (
3H, I++).

Light brown syrup (92%) lH-NMR (200MHz, CDC (2s) δ: 1
．． 16 (3H, t).

1.23 (3H, t), 3.59 (2H, q), 4
．． 21 (2H, q), 4.82 (2H, s), 5.
99 (2H, s), 6.99 (2H, d), 7.2
4-7.45 (5H, m), 7.55-7.75 (3
H, m), 7.98 (IH, dd) Reference Example 91 Pale yellow syrup (72%) "HNMR (200 MHz, CDCL) δ: 1.20
(3H, t).

2.18 (3H, s), 3.90 (2FI, s),
4.20 (2H, q), 5.96 (2H, s), 7
．． 01 (2H, d), 7.23-7.35 (IH)
, 7.377.50 (4H, m), 7.59-7.
80 (3H, m), 7-97 (IH, dd) Reference example 9
2 Light brown syrup (88%) 'HNMR (200MHz, CDCL) δ: 1.20
(3H,L).

1.27 (3H, t), 2.62 (2H, q), 3
．． 96 (2H, s), 4.20 (2H, q), 6.
00 (2H, s), 7.01 (2H, d), 7.2
9 (IH, t).

7.38-7.49 (4H, m), 7.57-7.7
8 (3H, m), 7.96 (IH.

dd) Reference Example 93 Light brown syrup (99%) Reference Example 94 Dinyl-4-yl) methylcoaminobenzoate (5 g
) and N a H (60% oil, 1.62 g) were dissolved in methanol (50 ml) and stirred at room temperature for 24 hours.

The syrup obtained by concentrating the reaction solution was mixed with saturated NaHCO
, aqueous solution (loOml) and the mixture was extracted with chloroform. Wash the organic layer with water.

The crude crystals obtained by drying and concentrating were recrystallized from ethyl acetate-hexane to obtain colorless crystals (3.9 g, 82%).

Melting point 106-108°C 'H-NMR (200MHz, CDCl25) δ: 3
．． 81 (3H, s).

3.97 (2H, br s), 4.23 (2H, s)
, 6.40 (IH, br s).

6.88-6.91 (2+(, m), 7.34-7.
55 (7H, +11), 7.64 (1) 1°at),
7.77 (lH, dd) I R (KBr) cm"': 3410.3350.2
225.1695.1485゜1470, 1290.1
200. 780. 760 Reference Example 95 Ethyl 3-amino-2-[(2'-cyanobihumidazole-7-carpoxylate methyl 3-amino-2-[(2'-cyanobiphenyl-4-yl)methylcoaminobenzoate (0.5g)
3-chloropropionyl chloride (0.15 ml) was added dropwise to the CH, C1 solution (5 ml) under water cooling. The mixture was stirred at room temperature for 30 minutes and the resulting residue was dissolved in methanol (5 ml) containing concentrated hydrochloric acid (0.5 ml).
l) and stirred at room temperature for 16 hours. The residue obtained by concentrating the reaction solution was dissolved in CHxC1*HzO, and the aqueous layer was made alkaline for extraction. Wash the organic layer with water.

Dry and concentrate to create light brown syrup (0.7g, 100%)
I got it.

"H-NMR (200MHz, CD0ff,) δ: 3
．． 37 (2H, t).

3.74 (3H, s), 4.09 (2H, t), 5
．． 87 (2H, s), 7.00 (2H, d), 7.
29 (IH, t), 7.39-7.81 (7H, m)
, 7.97 (IH, dd) Reference Example 96 Methyl 2-(2-chloroethyl)-1-[(2'cyanobiphenyl-4-yl)methyl 1-benzimidazole-7-carpoxylate (1,0 g) and IC03
(0-25 g) was dissolved in methanol (30 ml), the mixture was heated under reflux for 2 hours, and the resulting residue was concentrated.
H, CI. The insoluble matter was filtered off. The syrup obtained by concentrating the filtrate was purified by silica gel column chromatography to obtain pale yellow syrup (0.45 g, 59%).
I got it.

'HNMR (200MHz, CD CQs) δ: 3.
19 (2H, t) 3.34 (3H, s), 3.72 (
3H,s), 3.92(2H,t), 5.88(2
H,s), 7.00(2H,d), 7.26(IH
,t), 7.40-7.48(4H,m), 7.5
6-7-76 (3H, m), 7.95 (lH, dd)
Reference Example 97 Synthesized in the same manner as Reference Example 96.

Colorless powder (1.1g, 93%) 'HNMR (200MHz, CDCQs) δ: 2.1
4(3)1. s) 3.02-3.11 (2H, m),
3.16-3.25 (2F1.m), 3.74 (3H
s), 5.86 (2H, s), 7.00 (2H, d
), 7.28(IH,t), 7゜39-7.49(
4H, m), 7.58-7.78(3)1. m),
7.97 (IH, dd) Reference example 98 7.62 (IH, m), 7.73-7.77 (2H,
m)IR(Neat)am-': 2210.1
515.1480.1460°1440, 1405.
1360. +330. 1275. 10058
40, 785. 760 Reference Example 99 2-Butyl-1-[(2'-cyanobiphenyl-4-yl)methyl]-7-chloromethylbenzimidazole (
0.65 g) and dimethylamine (50% aqueous solution, 1.5
m1) was dissolved in ethanol (3 ml), sealed in a tube, and heated for 5 hours. The syrup obtained by concentrating the reaction solution was dissolved in ethyl acetate and washed with water.

The syrup obtained by drying and concentrating was purified by silica gel column chromatography to obtain colorless syrup (0.4 g,
63%).

"H-NMR (200MHz, CDC et al. M: 0.9
2 (3H, t).

1.35(,53(2H,m), 1.18-1.94
(21, m), 2-16 (6H.

s), 2.80 (2H, t), 3.34 (2H, s
), 6.00 (2H, s), 6.95-7.01 (3
H, m), 7.16 (IH, t), 7.39-7.
50 (4H, m).

3-Amino-2-[(2'-cyanobiphenyl 4-yl)methylcoaminobenzoate (1.1 g) and ethyl methyl acetic anhydride (0.56 g) were dissolved in pyridine (2 ml) and heated at 115 °C for 15 min. heated for an hour. The reaction mixture was digested with ethyl acetate (15 ml), washed with water, dried and concentrated, and the resulting syrup was dissolved in ethanol (15 ml) containing concentrated hydrochloric acid (0.5 ml) and heated under reflux for 3 hours. The syrup obtained by distilling off the solvent was purified by silica gel column chromatography to obtain a pale yellow syrup (
1.2 g (92%) was obtained.

"HNMR (90MH2, CDCl23) δ: 0.9
0 (3H, t).

1.20 (3H, t), 1-40 (3H, d), 1
．． 50-2.10 (IH, m).

4.17 (2H, q), 5.87 (2H, s), 6
゜97 (2H, d), 7,178.03 (9H, m) I R (Neat) cm-': 2975.293
0.2875.2220141110, 1445.
1410. 1370. 1280. 1260°12
00, 1140.1100.1035. 760 Reference Example 100 Synthesized in the same manner as Reference Example 99.

Pale yellow syrup (quantitative) 'HNMR (90MHz, CDCL) δ: 1.03 (
6H, a).

1.20 (3H, t), 2.07-2.53 (IH,
m), 2.80 (2H, d).

4.17 (2H, q), 5.83 (2H, s), 6
．． 93(21(,d), 7.13-8.00(9H,
m) IR(Neat)am-': 2960.221
5.1710.1480°1400, 1280.125
5.1200.1120. 760 Reference Example 101 Tiltetrazol-5-yl)biphenyl-42-butyl-1-[[2'-(IH-tetrazol-5-yl)
biphenyl-4-yl]methyl]benzimidazole-
7-carboxylic acid (3,0 g), triphenylmethyl chloride (1,96 g) and triethylamine (1
,0ml) in CHtc I xc20ml),
Stir at room temperature for 16 hours.

The reaction solution was washed with water, dried (Na, 5O4), and concentrated, and the resulting residue was purified by silica gel column chromatography to obtain a colorless powder (4.25 g, 91%).

Melting point 120-123°C 'HNMR (200MHz, CDC45) δ: 0.8
8 (3H, t).

1.26-1.45 (2H, +n), 1.72-1.
88 (2H, m), 2.81 (2H, s), 5.7
2 (2H, s), 6.63 (2H, d), 6.92
-6.97 (8H, m), 7.12-7.43 (
13H, +i), 7.68(1)1. d).

7.78-7.83 (LH, m), 7.92 (L
H,d)IR(Neat)cm-': 3050
．． 2950.2925.1690°15951510,
1490.1440.1405.1275°1240,
1180. 740. 690 Example 1 Methyl 2-butyl-1-[(2'-cyanobiphenyl-4-yl)methyl]benzimidazole 7-carpoxylate (3.2 g), sodium azide (7.4 g)
and ammonium chloride (6.1 g) in DMF (301
111) and stirred at 115°C for 4 days. After adding water to the reaction solution, it was made acidic to about pH 3 to 4 with 1N hydrochloric acid, and the precipitated crude crystals (1) were purified by silica gel column chromatography. The obtained crystals were recrystallized from ethyl acetate-methanol to give colorless prism crystals (2.27 g,
63%). Melting point 168-169℃ Elemental analysis CasH24N IO!・C as H2O
(%) H (%) N (%) Calculated value: 66.37; 5.57;
17.86 Actual value: 66.04 i 5.6
9, 17.58'H-NMR (200MHz, D
MS〇-ds) δ: 0.88 (3H, t), 1.2
8-1.46 (2H, m), 1.65-1.80 (2
H, m) 2.82 (2H, t), 5.85 (2H, s
), 6.79 (2H, d), 7.00 (2H, d)
, 7.24 (IH, t), 7.45 (5H, m),
7.83(1)1. dd)I R(KBr)cm-'
: 1720.1600.1510.1455.128
5゜1255, 1240.775.755.745Example 2 The crude crystals (1) obtained in Example 1 were purified by silica gel column chromatography, and the resulting crystals were purified with ethyl acetate.
Recrystallized from hexane to give colorless needles (0.17 g, 4.
7%).

Melting point 133-135℃ Elemental analysis value CzyHxsN*○, C (%)
H (%) N (%) Calculated value: 69.51; 5.62; 1
8.01 Actual value: 69.47; 5.66
; 17.92'HNMR (200MHz, CD
CQs) δ: 0.94 (3H, t).

1.35-1.55 (21, m), 1.78-1.
93 (2H, m), 2.96 (2H, t), 3.1
5 (3B, s), 5.82 (2H, s), 6.81
(2H, d).

6.97 (2H, d), 7.25 (IH, t), 7
．． 48-7.67 (4H, m).

7.80 (IH, dd), 7.95 (IH, dd) I
R(KBr)am-': 1715.1520.14
15.1290.1260°1200, 1125.7
80.750 Example 3 Quinamide 2-butyl-1-[[2'-(L H-tetrazole-
5-yl)biphenyl-4-yl1methyl]benzimidazole-7-carboxylic acid (0,71 g) and diethyl cyanophosphate (90% purity, 0.82 g) in DMF (
After stirring the solution under water cooling for 1 hour, isopropylamine hydrochloride (0.14 g) and triethylamine (
0.61 g) was added and stirred at room temperature for 2 hours. Water was added to the reaction solution, neutralized with IN=hydrochloric acid, and then extracted with ethyl acetate. The organic layer was washed with water, dried, and then concentrated to dryness.

The obtained crude crystals were recrystallized from methanol-ethyl acetate to obtain colorless prism crystals (0.31 g, 41%).

Melting point 247-249℃ Elemental analysis value C! C (%) H (%) N (%) Calculated value as 5H32NTO・115H20: 69.91; 6.55;
19.68 Actual value: 69.91; 6.
30, 29.87'H-NMR (200MHz,
DM S 0-da) δ: 0.87 (3H, t),
0.93 (6H, d), 1.26-1.44 (2H,
m), 1.62-1.77 (2H, m), 2.80
(2H, t), 3.85-3.95 (IH, m), 5
．． 67 (2H, s), 6.84 (2H, d), 6.
99 (2H, d), 7.16-7.24 (2H, m)
, 7.44 (1B, d), 7.51-7.72 (4
H, m).

8.27 (IH, d) I R (KBr) cm-”: 1840.1540.1
510.1455.1415゜755,740 Example 4 Dimidazole-7-carboxylic acid disodium 2-butyl-1-[2'-(LH-tetrazol-5-yl)
Biphenyl-4-yl 1 methylbenzimidazole-7
-carboxylic acid (0.2 g), NaOMe (46 mg)
The mixture was added to methanol (15 ml) containing 100 ml of alcohol, and the mixture was stirred at room temperature for 15 minutes. Toluene (30ml) was added, and the mixture was directly concentrated under reduced pressure to distill off methanol.

The precipitated crystals were collected by filtration and colorless powder crystals (0.14 g).

62%).

Melting point 255-257℃ (decomposition) Elemental analysis value CsaHssN aNalo z ・2
C (%) H (%) N (%) Calculated value as Hto: 58.64; 4.92; 1
5.78 measured chain: 58.98; 4.60,
15.66'H-NMR (200MHz, DM
S O-da)a: 0.85(31(,t),
1.27-1.39 (2H, m), 1.59-1.7
4 (2H, m).

2.69 (2H, t), 6.10 (2H, s), 6
．． 81 (2H, d), 6.98-7.07 (3H, Cabinet), 7.19-7.53 (6H4) I R (K B
r) cm”= 1610.1410.1360.760
Example 5 2-Butyl-1-[[2'-(IH-tetrazole-5
-yl)biphenyl-4-yl1methyl]benzimidazole-7-carboxylic acid (0,47 g) and concentrated rL acid (0.
, heated under reflux for 66 hours in a 10,000 ml bottle. The solvent was distilled off, water was added to the residue, and 1N
-The pH was adjusted to about 3 to 4 with NaOH, and the mixture was extracted with ethyl acetate. After washing the organic layer with water and drying, the solvent was distilled off and the residue was purified by silica gel column chromatography. Recrystallized from ethyl acetate-hexane to give colorless prismatic crystals (0,
15g, 29%) was obtained.

Melting point 192-193℃ Elemental analysis value CsaHssN 10! as C (%)
H (%) N (%) Calculated value: 70.84; 6.34;
16.52 Actual value: 70.99 i 6.
46, 16.25'HNMR (200MHz, C
DCl23)δ: 0.83(3H,t)0.85(3
H, t), 1-18-1.39 (4B, m), 1.
45-1.64 (4Fl, m), 2.38 (2H, t
), 3.99 (2H, t), 5.50 (2H, s)
.

6.47 (2H, d), 6.79 (2H, d), 6
．． 93 (IH, d), 7.04 (IH, t), 7.
27-7.32 (IH, n+), 7.50 (IH, d
d), 7.56-7.68 (2H, m), 7.97
8.01 (IH, l11) I R (KBr) cm-'
: 1710.1465.1455.1415.128
01265, 1125.760 Example 6 (4-pyridyl)methyl 2-butyl-1-[(2'-
A toluene (loim) solution of cyanobiphenyl-4-yl)methyl]benzimidazole-7-carpoxylate (0.61 g) and trinotyltin azide (0.75 g) was heated under reflux for 4 days under a nitrogen stream. The residue obtained by distilling off the solvent was dissolved in ethanol (5-), and 1N-
Hydrochloric acid (8-) was added and stirred at room temperature for 5 minutes. IN-
The mixture was neutralized with aqueous caustic soda solution and extracted with ethyl acetate.

After washing the extract with water and drying, the solvent was distilled off, and the residue was purified by silica gel column chromatography. The obtained crystals were recrystallized from ethyl acetate-hexane to obtain colorless prismatic crystals (0.54 g, 83%).

Melting point 179-180℃ Elemental analysis value C32H21N 702 (%)
H (%) N (%) Calculated value: '70.70;5.38; 1
8.04 Actual value: 70.96; 5.45
; 1g, 02'HNMR (200MHz, CD
Cl2s) δ: 0.80 (3H, t).

1.18-1.36 (2H, m), 1.53 1.6
8 (2H, m), 2.49 (2H, t), 5.19
(2H,s), 5.51(2H,s), 6.44(
2H, d).

6.79 (2H, d), 7.15-7.31 (4H,
嘗), 7.47-7.61 (3H, +m), 7.6
7 (1B, dd), 7.92 (IH, dd), 8.
35(2H,d)IR(KBr)c+o-': 17
20.1600.1410.1280.1250゜11
20,760.750.740 Example 7 2-propyl-1-[[2'-(IH-tetrazole-
5-yl)biphenyl-4-yl]methyl 1-bemethyl
2-propyl-1-[(2'-cyanobiphenyl-4-
Methyl 1-benzimitazole 7-carpoxylate (2,5 g), sodium azide (3,9 g) and ammonium chloride (3,2 g) in DMF (30 m) at 110°C to 120°C for 5 days. Stirred. After adding water to the reaction solution, the mixture was acidified to about pH 3 to 4 with IN-hydrochloric acid and extracted with ethyl acetate. After washing the organic layer with water and drying, the solvent was distilled off and the resulting residue was purified by silica gel column chromatography. The obtained crystals were recrystallized from DMF-ethanol to obtain colorless crystals (0.8 g, 23%).

Melting point 275-276℃ (decomposition) Elemental analysis value C*1HzxNsOx・l/2H! C as O (%) H (%) N (%) Calculated values: 67.10, 5.18, 18
．． 78 actual measurements: 67.19, 4.95,
18.84'HNMR (90MHz, CDCl25
CFsCOOH)δ: 1.10(38,t),
1.70-2.20 (2H, m), 3.23 (2H.

t), 5.97 (2H, s), 6.90 (2H, d
), 7.13 (2H, d), 7゜47-7.80 (
5H, m), 8.03 8.17 (2H, m) I R
(KBr) cm-': 3070.2720.2440
．． 1700. 1450°1410, 1405.
1285.1235. 1200. 1190. 11
20 Example 8 Methyl 1-[(2'-cyanobiphenyl-4-yl)
Methyl 1-2-pentylbenzimidazole-7-carpoxylate (3,25 g), sodium azide (2,
6 g) and ammonium chloride (2.1 g) in DMF
(20d), the mixture was stirred at 110 to 120°C for 5 days.

After adding water to the reaction solution, it was made acidic to about pH 3 to 4 with IN-hydrochloric acid, and extracted with ethyl acetate. After washing the organic layer with water and drying, the solvent was distilled off and the residue was purified by silica gel column chromatography. The obtained crystals were recrystallized from ethyl acetate-ethanol and then treated with hot water to obtain colorless powder crystals (1.0 g, 29%).

Melting point 205-207°C (decomposition) Elemental analysis value Cz7H2sN no x・115H20
As C (%) H (%) N (%) Calculated value: 68.98; 5.66;
17.88 Actual value: 69.14; 5.
60; 17.90'H-NMR (90MHz,
CD CQs - CF sCOOH) δ: 0.87 (
3H,t), 1.13-1.53(4H,m), 1
．． 67-2゜10 (2H, m), 3-27 (2H, t
), 6.00 (2H, s), 6.93 (2H.

d), 7.17 (2H, d), 7.47 7.90
(5H, m), 8.07-8゜20 (2H, m) I R (Nujol) cm''': 3040.277
5.1695.1485゜1450, 1425.141
0.1290.1240.1200.755 Example 9 Poxylate Methyl 2-butyl-1-[(2'-cyanobifuniniru-4-yl)methyl]-5-methylbenzimidazole-7-carpoxylate (2,8 g ), sodium azide (6.2 g) and ammonium chloride (5.1 g) were added to DMF (251112) and stirred at 110120°C for 3 days. Dilute the reaction solution with water and adjust the pH with JN-hydrochloric acid.
After making the mixture acidic to about 3 to 4, it was extracted with ethyl acetate. After washing the organic layer with water and drying, the solvent was distilled off and the residue was purified by silica gel column chromatography. Obtained t;
The crystals were recrystallized from ethyl acetate-methanol to obtain colorless prismatic crystals (0.72 g, 24%).

Melting point 144-145℃ Elemental analysis value C2* H! s N @ O!・0.1
C (%) H (%) N (%) Calculated value as H20: 69.72; 5.89, 17
．． 42 Actual value: 69.58; 5.89
, 17.28'H-NMR (200MHz, CD
C(Is)δ: 0.82 (3H, t).

1.17-1.37 (2H, m), 1.45-1.6
0 (2H, m), 2.26 (3H, s), 2.34
(2H, t), 3.56 (3H, s), 5.23 (
2H,s).

6.43 (2H, d), 6.60 (IH, s), 6
．． 76 (2H, d), 7. -28-7.32 (2H,
m), 7.59-7.69 (2H, m), 7.96
-8.00 (IH, m) I R (KBr) cm-': 1715. 1515
．． 1455. 1440. 14101315, 1
255. 1225. 1050.785.765 Example 10 Methyl 2-butyl-5-methyl-1-[[2'-(I
H-tetrazol-5-yl)biphenyl-4-yl 1
Methyl 1-benzimidazole-7-carpoxylate (
0.15g) was mixed with IN-caustic soda aqueous solution (1.2ml
The mixture was heated under reflux for 2 hours in a mixture of 2) and methanol (2-). The reaction solution was diluted with water, washed with ether, and then acidified to about pH 3 to 4 with 1N hydrochloric acid. The precipitated crystals were collected by filtration and recrystallized from ethyl acetate to give colorless crystals (0°Ig, 71
%) was obtained.

Melting point 175-178℃ (decomposition) Elemental analysis value CzyHzaNso! ” 1/2H
C (%) H (%) N (%) Calculated value as so: 6g, 19; 5.72,
17.67 actual value + 68.25; 5.6
6; 17.59'HNMR (200MHz, D
MSOda) δ: 0.87 (3H, t), 1.25
-1.44 (2H, m), 1.63-1.77 (2H
, m) 2.41 (3H, s), 2.79 (2) 1. t
), 5.82 (2H, s), 6.76 (2H, d)
, 6.99 (2H, d), 7.45-7.49 (2
H, m) 7.55-7.69 (4H, m) I R (KBr) cm-': 3440. 1700.
1600 1515. 14501410, 131
0. 1240.765 Example 11 Ruboxylate 6-methyl-3-nitro[N-(2'-(N-1-riphenylmethyltetrazol-5-yl)biphenyl-
4-yl) methyl-N-valeroyl ethyl anthranilate (2,1 g), iron powder (0,73 g), salt production @ (2,
A mixture of 1II12) and ethanol (10m) was heated under reflux for 18 hours. After filtering the insoluble matter in the reaction solution, the filtrate solution was concentrated to dryness. The residue was dissolved in IN-sodium hydroxide solution, and the precipitate separated out was filtered through Celite. After the furnace solution was acidified with concentrated hydrochloric acid, the separated oil was extracted with methylene chloride.

The extract was washed with water and concentrated to dryness, and the resulting syrup was purified by silica gel column chromatography.

The residue obtained from the eluate was crystallized from ethyl acetate-isopropyl ether to give astringent brown prism crystals (0.8 g, 5
9%).

Melting point 164, -165°C 'HNMR (200MHz, CDCMs) δ: 0.8
4.1.06 (each 3H, t), 1.20 1
．． 39 (2H, m), 1.48 1.63 (2H, m
), 2.32 (3H, s), 2.38 (2H, t)
, 3.88 (2H, q).

5.28 (2H, s), 6.56 (2H, d), 6
．． 74 (LH, d), 6.86 (3H, da), 7
．． 28-7.33 (IH, m), 7.58-7.63
(2Hm), 7.91-7.97(II(,m) Example 12 Boxylate methyl 5-chloro-3-nitro-2-[N-[2'
-(N-triphenylmethyl-IH-tetrazole-5
-yl)biphenyl-4-yl]methyl]-N-valerylanthranyl M (1,26 g) nomethanol (1!M
2) Add concentrated hydrochloric acid (1,611I12) and iron powder (
95% purity, 0.45 g) was added and heated under reflux for 20 hours. Insoluble matters were removed by filtration, the filtrate was concentrated, and then extracted with ethyl acetate and water. After adding sodium bicarbonate water to the organic layer and filtering off the generated insoluble matter, the organic layer was washed with water, dried, and concentrated. The obtained residue was purified by silica gel chromatography, and the obtained crystals were recrystallized from ethyl acetate-benzene to give colorless crystals (
0.59 g, 74%) was obtained.

Melting point 132-133℃ Elemental analysis value C27H□N, ○, C as CI2 (%)
H (%) N (%) Calculated value: 64.73; 5.03; 16
．． 77 Actual value: 64.49; 5.06
, 16.50'H-NMR (200MHz, CD
C10) δ: 0.84(3)1. t).

1.23-1,41 (2H, m), C52-1,68
(2H, m), 2.50 (2H, t), 3.62 (
3H,s), 5.48(2H,s), 6.46(2
H, d).

6.83 (2H, d), 6.93 (LH, m), 7
．． 31-7.36 (IH, +n).

7.49 (IH, d), 7.63 7.68 (2H,
m), 7.96 8.00 (IH, m) T R (KBr) cm”: 2960.2875.17
20.1510.1460°1430, 1400.12
80.1230.1190.750 Example 13 Methyl 2-butyl-5-chloro-1-[[2'-(I
H-tetrazol-5-yl)biphenyl4-yl]methyl]benzimidazole-7-carpoxylate (0
, 28 g) in methanol (4-), IN-caustic soda aqueous solution (2-) was added and stirred at room temperature for 16 hours.

After concentrating the reaction solution, the residue was dissolved in water (10 ml) and acidified with IN-hydrochloric acid. Filter the precipitated crystals,
Recrystallization from methanol-chloroform gives colorless crystals (0
, 2g, 72%) was obtained.

Melting point 232-234℃ Elemental analysis value C25H1sN602CI2・l/2Hz
C as O (%) H (%) N (%) Calculated value: 6
2.96; 4.88; 16.94 actual value +
63.01; 4.81; 16.87'
H-NMR (200MHz, DMSOda) δ: 0.
87 (3H, t), 1.26-1.45 (2H, m
), 1.64-1.79 (2M, m).

2.82 (2H, t), 5.81 (2H, s), 6
．． 78 (2H, d), 7.00 (2H, d), 7.
45-7.69 (5Hm), 7.91 (IH, d)I
R(KBr)cm-': 2975.2930.28
75. 1705. 14801460, 1400.1
270. 1240. 1220. 1190.870
゜760, 740 Example 14 Ethyl 2-butyl-1-[(2'-cyanobifurnidyl-4-yl)methyl 1-benzimidazole-7-carboxylic acid (0.21 g), sodium azide (1.3 g) and ammonium chloride (1,07 g) in DMF (8-)
The mixture was stirred at 110-120°C for 60 hours. After adding water, the mixture was acidified to about pH 3 to 4 with IN-hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with water, dried, and concentrated to dryness. Ether was added to the residue, and the crude crystals were collected by filtration and recrystallized from ethanol to obtain colorless crystals (95 mg, 41%).

Melting point 138-139℃ 'H-NMR (90MHz, CDCρ3) δ: 0.8
0 (3H, t).

1-07-1.77(7)1. m), 2.37(2
H,t), 4.07(2H,q).

5.50 (2H, s), 6.47 (2H, d), 6
．． 80 (2H, d), 7.00-7-10 (2H, m
), 7.23-7.73 (4H, Su, 7.90-8
°10 (lH, m) I R (Nujol) cm-I: 1715.1410
．． 1290.12601125, 1040.750 Example 15 Ethyl zimidazole-7-carboxylate 2-butyl-1-[[2'-(I H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7- Carboxylic acid (80 mg) in 2-
Dissolved in methoxyethanol (1,5Ilj2), 2N
- Add caustic soda aqueous solution (1,5-) to 110-
The mixture was stirred at 120°C for 1 hour. The reaction solution was neutralized by adding 2N hydrochloric acid, and concentrated to dryness. The residue was dissolved in chloroform, insoluble materials were removed by filtration, and then concentrated to dryness. The obtained crude crystals were recrystallized from aqueous ethanol to give colorless crystals (60 mg, 77
%) melting point, 'H-NMR and IR were in good agreement with those obtained in Example 1.

Example 16 2-Butyl-1-[(2'-cyanobiphenyl-4-yl)methyl 1-7-hydroxymethylbenzimidazole (0,4 g), sodium azide (0,98 g) and ammonium chloride (0, 8g) in DMF (4d),
Stirred at 110-120°C for 4 days.

Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. After washing the extract with water and drying, the solvent was distilled off, and the residue was recrystallized from ethyl acetate-methanol to obtain colorless needles.

Melting point 152-153℃ Elemental analysis value C1HzsN so ” l/2CaHs
o2・1/10H, O as C (%) H (%) N (%) Calculated value: 69.43; 6.28; 1
7.35 Actual value: 69.14; 6.22;
17.59'HNMR (200MHz, DMSO-
da) δ: 0.86 (3H, t), 1.26 1-
44 (2H, +a), 1.63-1.78 (2H, m
).

2.76 (2H, t), 4.47 (2H, s), 5
．． 47 (IH, br s), 5.76 (2Ls),
6.81 (2H, d), 7.04 (2H, d), 7
．． 08-7.16 (2H, ++), 7.49-7.7
0(5H,m)I R(KBr)Cm″″’: 151
0.1450.1405.1020.755゜Example 1
7 Ethyl [[2-butyl-1-[2'-(IH-tetrazol-5-yl)biphenyl-4-yl]toethyl 2-butyl-1-[(2'-cyanobiphenyl-4-yl)methyl 1 Benzimidazole 7-carpoxylate (0,86 g), sodium azide (0,5 g
) and ammonium chloride (1.6 g) in DMF (10
It was stirred at 110-120°C for 4° for 5 days.

Water was added to the reaction mixture, the mixture was acidified to pH 3-4 with IN-hydrochloric acid, and extracted with ethyl acetate. After washing the organic layer with water and drying, the solvent was distilled off.

The obtained residue was purified by silica gel column chromatography, and the obtained crude crystals were recrystallized from ethyl acetate to obtain colorless needle crystals (0.53 g, 56%).

Melting point 129-130℃ Elemental analysis value C*sHsoN soz ・0-4Ht
o as C (%) H (%) N (%) Calculated value: 69.41; 6.19; 1
6.75 Actual value: 69.50; 5.94;
17.03'H-NMR (200MHz, CDC
et al.) δ: 0.83 (3H, t).

1.12-1.33 (5H, m), l-48-1,6
3 (2H, m), 2.24 (2H, t), 3.41
(2H, s), 4.03 (2H, q), 5.46 (
2H,s).

6.55-6.66 (3H, m), 6.87 (2H,
d), 6.93-6.99 (2H, m), 7.28
-7.32 (LH, m), 7.55-7.68 (2M
, m).

7.95-7.99 (IH, m) I R (KBr) c+n-': 1740.1720.
1510.1410.1280°1255, 1145.
755.740 Example 18 Ethyl 2-butyl-1-[[2'-(IH-tetrazol-5-yl)biphenyl-4-yl)methyl]benzimidazole-7-acetate (0,28 g) IN
- Heating under reflux for 2 hours in a solution of caustic soda aqueous solution (1.5d) and methanol (5d).

After concentrating the reaction solution, it was neutralized with 1N-hydrochloric acid. The precipitated crystals were collected by filtration and purified by silica gel column chromatography to yield colorless crystals (0.12 g).

46%).

Melting point 170-171℃ Elemental analysis value C27HzaN C as 602 (%)
H (%) N (%) Calculated value: 69.51; 5.62;
18.01 Actual value: 69.60; 5.
78; 17.90'HNMR (200MHz,
DMS Ods) δ: 0.87 (3H, t), 1.
27-1.44 (2H, m), 1.64-1.75 (
2H, m) 2.79 (2H, t), 3.58 (2H,
s), 5.62 (2H, s), 6.80 (2H, d
), 6.98-7.16 (4H, m), 7.49-
7.71 (5H, m) I R (KBr) cm"': 3
430.1720.750 Example 19 Mu salt 2-butyl-1-[(2'-cyanobiphenyl-4-yl)methyl]-7-medoxymethylbenzimidazole (0.6 g) and trimethyltin azide (1 2 g) was heated under reflux in toluene (12 m) for 3 days. The solvent was distilled off, IN-hydrochloric acid (8d) was added to the residue, and after stirring for a while, the mixture was extracted with ethyl acetate.

The organic layer was washed with water, dried, and the solvent was distilled off. The residue was purified by silica gel column chromatography.

The obtained oil was dissolved in ethyl acetate, a methanol solution of 2-ethylhexanoic acid sodium salt (0.25 g) was added, and the mixture was concentrated. The precipitated crystals were recrystallized from toluene-ethyl acetate to obtain colorless crystals (0.22 g, 31%).

Melting point 175-178℃ Elemental analysis value C,,H,,N,0Na-H,C as O
(%) H (%) N (%) Calculated value: 65.84; 5.93;
17.06 Actual value: 65.94; 5.
81; 17.06'HNMR (200MHz,
CDC(Is)a: 0.70 (3H,t).

1.06-1.25 (2M, m), 1.50-1.6
5 (2H, +m), 2.49 (2H, t), 2.8
6 (3H, s), 4.21 (2H, s), 5.27
(2H, s).

6.41 (2H, d), 6.73-6.77 (3H,
m), 6.92-7.00 (2t(, m), 7.1
9-7.30 (2H, m), 7.37 (LH, d),
7.62 (lH, d) I R (KBr) cm-'+ 1510. 1455
．． 1420. 1405. 1350°1280,
1080. 740 Example 20 2-Butyl-1-[(2'-cyanobiphenyl-4-yl)methyl]-7-medoxybenzimidazole (0,
A solution of trimethyltin azide (1.6 g) and trimethyltin azide (1.6 g) in toluene (15 m) was heated under reflux for 44 hours.

The precipitated crystals were collected by filtration, dissolved in methanol (20 iIft), IN-hydrochloric acid (8-) was added, and the mixture was stirred at room temperature for 5 minutes. Water was added to the reaction solution, extracted with ethyl acetate, and the organic layer was washed with water and dried. The solvent was distilled off, and the residue was purified by silica gel column chromatography. The obtained crude crystals were recrystallized from ethyl acetate-methanol to give colorless prism crystals (0.83 g).

87%).

Melting point 189-190℃ Elemental analysis value C (%) as C1H□Neo -HCQ
H (%) N (%) Calculated value: 65.75
, 5.73; 17.69 Actual value: 6
5.46; 5.85; 17.44'H
NMR (200MHz, DMSOda) δ: 0.87
(3H, t), 1.26-1.44 (2H, +n),
1.61-1.76 (2H, m) 3.1.4 (2H,
t), 3.83 (3H, s), 5.82 (2H, s
), 7.07-7.18 (5H, m), 7.38 (
IH, d), 7.45 7.73 (5H, m) I R
(KBr) cm-': 1615.1550.1490
．． 1455.1440°1355, 1275.1260
．． 1130.1100.1060.990°870,8
50.775.750.730 Example 21 Ethyl 2-butyl-6-methyl-1-[[2'-(IHtetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylate ( 0.55g
), a mixture of 5N sodium hydroxide solution (5-) and ethanol (10+72) was heated under reflux for 100 hours. After the reaction solution was concentrated to dryness, the residue was dissolved in water, and then acidified with concentrated hydrochloric acid. The precipitate was collected and dichloromethane-
Washed with methanol mixture. Saturated 1 Sod water was added to this precipitate to dissolve it, and insoluble matter was filtered. After making the furnace solution acidic with concentrated hydrochloric acid, the precipitate was separated and recrystallized from hydrous dimethylformamide to give colorless crystals (0.22 g, 4
2%).

Melting point 298-299°C 'HNMR (200MHz, CDCff5) δ: 0.
85 (3H, t).

1.23-1.43 (2H, m), 1.58-1.7
5 (2H, +n), 2.38 (3H, s), 2.7
0(2)1. t), 5-47 (2H, s), 6-8
7.7.02 (each 2H, d), 7.07 (1
8, d), 7.45-7.71 (5B, m) elemental content t
R value CxrHt*N *Os ” C (%) H (%) N (%) Calculated value as l/IOHno: 69.24; 5.64; 17
．． 94 actual value: 68.97; 5.85
17.81 Example 22 Methyl]benzimidazole 2-butyl-1-[(2'-(cyanobiphenyl4-yl)methyl]-7-methylbenzimidazole (0,5
g), sodium azide (1,3 g) and ammonium chloride (1,1 g) in DMF (5d) at 110-12
The mixture was stirred at 0°C for 3.5 days. Add water to the reaction solution and incubate
After acidifying with hydrochloric acid to pH 3 to 4 and extracting with ethyl acetate, the organic layer was washed with water and dried. The residue obtained by distilling off the solvent was purified by silica gel column chromatography, and the obtained crystals were recrystallized from ethyl acetate-methanol to obtain colorless crystals (0.36 g, 62%).

Melting point 222-224℃ Elemental analysis value CxaH**Ns・l/4C<C as HaOt (%) H (%) N (%) Calculated value: 72.95 : 6.35;
18.90 Actual value: 72.80; 6.3
5; 19.02 Kame HNMR (200MH2,C
DCl23) δ: 0.80 (3H, t).

1.14-1.32 (2H, m), 1.44-1.5
9 (2H, m), 2.14 (2H, t), 2.26
(3H,s), 5.32(2H,s), 6.48-
6.56 (3H, m), 6.83-6J9 (4H, m
), 7.29-7.34 (LH, m).

7.55-7-68 (21 (, m), 7,92 7
．． 97(IH,m)r R(KBr)cm-'+ 1
510 1450. 1410. 78 (1,750 Example 23 Lard ethyl 1-[(2'-cyanobiphenyl-4yl)methyl J-2-isopropylbenzimidazole-7-carpoxylate (2,12 g), sodium azide (3,9
g) and ammonium chloride (3.2 g) in DMF (1
5d) at 110-120°C for 5 days. water(
After adding 150m) and adjusting the pH to about 3 to 4 with dilute hydrochloric acid,
Extract with ethyl acetate.

The organic layer was washed with water, dried, and then concentrated to dryness. The residue was crystallized from ethanol to give colorless prism crystals (1.2 g).

52%).

Melting point 144-146℃ Elemental analysis value C2THKIN, 02・l/4C2Hs
o C as H・H,O (%) H (%) N (%) Calculated value: 66.58; 5.99;
16.94 Actual value: 66.38, 5.74
; 16.69'H-NMR (90MHz, CD
C et al-CFsCOOH) δ: 1.30 (3H, t),
1.53 (6H, d), 3.37-3.80 (IH
.

m), 4.30 (2H, q), 5.97 (2H, s
), 6.90 (2H, d), 7°13 (2H, d)
, 7.43-8.10 (7H, m) I R (Nujo
l) cm-': 1730.1450.1285.12
70.750 Example 24 Ethyl 1-[(2'-cyanobiphenyl-4-yl)
Methyl]-2-methylbenzimidazole-7-carpoxylate (2,5 g), sodium azide (3,9 g) and ammonium chloride (3,2 g) in DMF (30-)
The mixture was stirred at 110-120° C. for 4 days. The crystals obtained in the same manner as in Example 23 were recrystallized from ethanol to obtain colorless prism crystals (1.36 g, 49%).

Melting point 205-206℃ Elemental analysis value CzsH24N aox -215E
to H to C (%) H (%) N (%)
Calculated value: 67.82; 5.38;
18.39 Actual value: 67.64; 5.
38; 18.24'HNMR (90MHz, C
DC(IsCFsCOOH)δ: 1.27(4H
,t), 2.90(3H,s), 3.87(IH,
q), 4゜30(2H,q), 5.93(2H,s
), 6.93 (2H, d), 7.10 (2H.

d), 7.40-7.80 (5H, m), 8.00
(2B, d).

IR(Nujol)cm-': 1725. 141
0. 1290. 1260°1220, 1115.
1040. 750 Example 25 Ethyl 1-[(2'-cyanobiphenyl-4-yl)
methyl]-2-ethylbenzimidazole 7-carpoxylate (1,55 g), sodium azide (2,6 g) and ammonium chloride (2,14 g) in DMF (15+
m) at 110-120°C for 58 hours. The crystals obtained by the same treatment as in Example 23 were recrystallized from ethanol to obtain colorless prism crystals (0.68 g, 40%).

Melting point 188-189℃ Elemental analysis value C2iH24N so 2・215H20
As C (%) H (%) N (%) Calculated value: 67.93; 5.44;
18.28 Actual value: 67.76; 5.
36; 18.54'HNMR (90MHz, C
DCl2. CFsCOOH)δ: 1.33(3H
,t), 1.50(3H,t), 3.27(2H,
q), 4゜33(2H,q), 5.97(2H,s
), 6-93 (2H, d), 7.17 (2H.

d), 7.40 8.07 (7) 1. m)I R(N
ujol)am-': 1710.1285.1265
．． 755 Example 26 Ethyl 2-methyl-1-[[2'-(IH-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carpoxylate (0,64 g)
was heated under reflux for 4 hours in a mixture of methanol (101112) and 2N-caustic soda water (5t12).

After dissolving the residue obtained by concentration to dryness in water, IN-
When neutralized with hydrochloric acid, crystals precipitated. DMF-EtOH-
Recrystallize from H2O to obtain colorless prismatic crystals (0.3 g, 49
%) was obtained.

Melting point 283-284°C (decomposition) Elemental analysis value C23HIIN So x ・115H!
○ as C (%) H (%) N (%) Calculated value: 66.72 i 4.48;
20.30 Actual value: 66°96; 4.40
, 20.25'H-NMR (90MHz, CDCQ
s-CFsCOOH) δ: 2.97 (3H, s), 5
．． 97 (28, s), 6.97 (2H, d), 7.
17 (2H, d), 7.50-7.90 (5H, m)
, 8.10 (IH, d), '8.20 (LH, d) I R (Nujol) cm-': 2470.1700
．． 1455.1410°1240, 1220.990.
750 Example 27 2-ethyl-1-[[2'-(I H-tetrazole-
5-yl)biphenyl-4-ylcomethyl)ben 141
0 1290,1250.1210.755ethyl 2
-ethyl-1-[[2'-(IH-tetrazole-5-
yl)biphenyl-4-yl 1-methyl 1-benzimidazole-7-carpoxylate (0.5 g) was heated under reflux for 4 hours in a mixture of methanol (Ion) and 2N-caustic soda water (5iI12).

After dissolving the residue obtained by concentration to dryness in water, 1N-
When neutralized with hydrochloric acid, crystals precipitated. Recrystallized from DMF-ethanol-water to give colorless prism crystals (0-, 27g, 5
8%).

Melting point 261-262℃ Elemental analysis value C1H3゜N, O, C (%)
H (%) N (%) Calculated value: 67.63; 4.70 i
19.45 Actual value: 67.91; 4.75
; 19.80'H-NMR (90MHz, CD
Cl23-CF sCOOH)δ: l-50(3
H, t), 3.20 (2H, q), 5.97 (2H
,s), 6゜93(2H,d), 7.13(2)1
．． d), 7.37-8.17(7H,m)I R(N
ujol)cm-': 3070.2720.1700
．． 1450° Example 28 Ethyl 2-isopropyl-1-[[2'-(I H tetrazol-5-yl)biphenyl-4-ylcomethyl 1benzimidazole-7-carpoxylate (1,2
g) in methanol (5 m) and 2N-caustic soda water (5 m).
The mixture was heated under reflux for 4 hours in a mixture of mlI2). The residue obtained by concentration to dryness was dissolved in water and then neutralized with IN-hydrochloric acid to precipitate crystals.

Recrystallization from DMF-50% ethanol gave colorless prism crystals (0.8 g, 71%).

Melting point 265-267℃ (decomposition) Elemental analysis value ClSHzzN *O!・3/IOHs
o as C (%) HC%) N (%) Calculated value: 67.65; 5.13; 18
．． 93 actual value: 67.64; 5.07
; 19.00'HNMR (90MH2, CDCl
23 CF2COOH) δ: 1.67 (6H, d),
3.40-3,83 (IH, m), 6.00 (2H
.

s), 6.90 (2H, d), 7.13 (2H, d)
, 7.43-7.83 (5H.

m), 8.07 (2H, d) I R (Nujol) am-': 2620. 169
5. 12g5. 1260°1245, 1205.
760 Example 29 Salt 2-butyl-1-[[2'-(I H-tetrazole-
5-yl)biphenyl-4-yl 1methyl 1benzimidazole-7-carboxylic acid (1,2 g) and potassium 2-ethylhexanoate (1,3 g) in ethanol (50+d
) After adding toluene (50ml) to the solution, ethanol was distilled off. The precipitated crystals were collected by filtration and washed with ether to obtain colorless crystals (1.1 g, 79%).

Melting point 355-358℃ (decomposition) Elemental analysis value Cx*H! ! K x N so z ・Ht
C (%) H (%) N (%) Calculated values including o: 57.12; 4.42; 15.
37 Actual value: 56.93, 4.26;
15.01'H-NMR (200MHz, DMS○-
d6) δ: 0.86 (3H, t), 1.22-1
．． 43 (28, m), 1.60-1.76 (2H, m)
2.70 (2H, t), 6.06 (2H, s), 6
．． 79 (2H, d), 6.94-7.03 (3H, m
), 7.20-7.34 (4H, m), 7.40 (
IH, dd).

7.53-7.58(1)1. m) I R(KBr)am"": 3350.1600.1
570.1515.1460°1400, 1360.
1315. 1280. 1005. 825. 7
85゜Example 30 2-butyl-1-[[2'-(cyanobiphenyl-4-
yl)methyl]-7-hydroxypenzimidazole (
0.69 g) and trimethyltin azide (1°1 g) were heated under reflux for 4 days in toluene (15 wj2). The precipitated crystals were collected by filtration and mixed with IN-hydrochloric acid (10d) and methanol (
The mixture of 15d) was stirred at room temperature for 10 minutes. IN-
The pH was adjusted to about 3 to 4 with caustic soda water, and the precipitated crystals were collected by filtration. After the crude crystals were purified by silica gel column chromatography, the obtained crystals were recrystallized from acetone to obtain colorless crystals. Melting point 186-188℃ Elemental analysis value C,, H□N, C as 0.1/2H20
(%) H (%) N (%) Calculated value: 69.27; 5.81;
19.39 Actual value: 69.60; 5.6
9; 19.26'HNMR (200MHz, D
MSOda) δ: 0.84 (3H, t), 1.23
-1.41 (2H, m), 1.55-1.70 (2H
, m).

2.71 (2H, t), 5.68 (2H, s), 6
．． 60 (IH, d), 6.95 (IH, t), 7.
02-7.06 (5H, m), 7.48-7.70 (
4H, m).

10.00(IH,s) I R(KBr)am-': 1620.1490.1
460.1350.1295°780, 755. 73
0 Example 31 Chil 1benzimidazole-7-carboxylar 2-propyl-1-[[2'-(l H-tetrazole-5-
biphenyl-4-yl]methyl]benzimidazole-7-carboxylic acid (465 mg) and concentrated sulfuric acid (7,2
g) was heated under reflux in methanol (60t12) for 24 hours. The solvent was distilled off, water was added to the residue, and 1N-NaOH
The pH was adjusted to about 3 to 4 and extracted with ethyl acetate. After washing the organic layer with water and drying, the solvent was distilled off and the residue was purified by silica gel column chromatography. Recrystallization from ethanol gave colorless prism crystals (310 mg).

Melting point 195-196℃ Elemental analysis value C (%) H (%) N (%) Calculated value: 67.93; 5.44;
18.28'9! , Measured value: 68.02;
5.33; 18.33'HNMR (90MH
z, CD Cl2s) δ: 0.87 (3H, t).

1.37-1.80 (2H, m), 2.30 (2H,
t), 3.60 (3H, s).

5.47 (2H, s), 6.47 (28, d), 6
．． 80 (2H, d), 6.938.00 (7H, m) IR (Nujol) cm- 1270, 760 Example 32 1730, 1440. 1290. 1280° Synthesized in the same manner as in Example 5.

Melting point 185-186℃ Elemental analysis value CzsH2iNiCh・1/2 C, HI
O□H, C as O (%) H (%) N (%) 66.70; 5.47; 17.296
6.70; 5.26; 17.49 Actual value: Calculated value: Example 33 Synthesized in the same manner as in Lard Example 5.

Example 34 Methyl 2-butyl-1-[[2'-(LH-moto2-
Butyl-1-[[2'-(l H-tetrazol-5-yl)biphenyl-4-yl]methyl 1-benzimidazole-7-carboxylic acid (1,8 g) and concentrated sulfuric acid (14,4 g)
) in methanol (18 mI2) for 24 hours under reflux! ;. The solvent was distilled off, water was added to the residue, and I N -N
aOHf pH was adjusted to about 3-4 and extracted with ethyl acetate. After washing the organic layer with water and drying, the solvent was distilled off and the residue was purified by silica gel column chromatography. Recrystallized from ethanol to obtain colorless prism crystals (1.05g)
I got it.

Melting point 153-155℃ Elemental analysis value C,,H□N,O,・215H,O as C (%) H (%) N (%) Calculated value: 68.45; 5.70;
17.74 Actual value: 68.63; 5.
61;, 17.72'HNMR (90MHz,
CDCQ3) δ: 0.80 (3H, t).

1.00-1.73 (4H, m), 2.37 (2H,
t), 3.60 (3H, s), 5°47 (2H, s)
, 6.47 (2H, d), 6-80 (28, d),
6.97-800 (7H, m) I R (Nujol) cm-': 1720.1450
．． 1430.12901280, 1270.755 Example 35 - Synthesized in the same manner as in Example 14.

Melting point 128-130℃ Elemental analysis value C! 5HisNsOz” 215C*H
aOz ” C (%) H (%) N (%) Calculated value: 67.98; 6.06; 16.07 Actual value:
68.10; 6.07; 15.94 Example 36 Uniru-4-yl]methyl 1-benzimidazole-7-
Carpoquinlate 2-butyl-1-[[2'-(1,H-tetrazol-5
methylene chloride (
20m) solution of triphenylmethyl chloride (1,96
g) and triethylamine (1,0d) were added and stirred at room temperature for 16 hours. After washing the reaction solution with water and drying, the solvent was distilled off, and the resulting residue was purified by silica gel column chromatography to obtain a colorless powder (4.25 g). The obtained N-) lithyl compound was dissolved in DMF (5-), potassium carbonate (0.2 g) and pivaloyloxymethyl iodide (0.35 g) were added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated, and the residue was extracted with water and ethyl acetate.
The organic layer was washed with water and dried.

The residue obtained by distilling off the solvent was dissolved in methanol (10-), 1N-hydrochloric acid (3-) was added, and the mixture was stirred at room temperature for 1.5 hours. The reaction solution was concentrated to dryness, and the resulting residue was purified by silica gel column chromatography to obtain colorless powder crystals (0.43 g, 74%).

Melting point 202-105℃ Elemental analysis value Cs z H34NIQ a・l/2)
1. o as C (%) H (%) N (%) Calculated value: 66.77.6.13 i 14.60 Actual value: 66.76; 6.09; 14.45'H-NMR (
200MHz, CDCQ3) δ: 0.87 (3H,
t), 1.16 (9H.

s), 1.23-1.42 (2H, m), 1.57
-1.72 (2Fl, m), 2.53 (2H, t),
5.60 (2H, s), 5.70 (2H, s),
6.60 (2H, d) 6.89 (2) 1. d), 7.
11 (IH, t), 7.25-7.27 (IH, m)
.

7.33-7.38 (lH, m), 7.58-7.6
3 (3H, m), 7.97-8.02 (IN, m) IR (KBr) cm-I: 2975.1750.1
730.14801450, 1410. 1280.1
260.1150.1100. 1010950, 7
60. 750 According to Example 36, the following compounds were synthesized.

Example 37 Nzimidazole-7-carpoquinlate Yield 74% Melting point 102-105°C Elemental analysis C3-H3s Na Oi・115 C
HCQ, as C (%) H (%) N (%) Calculated value: 65.39; 5.95; 13.00 Actual value: 6
5.18; 5.99; 12.86'H-NMR (200
MH2, CDCl23) δ: 0.87 (3H, t),
1,171.87 (18H, m), 2.53 (2H
, t), 4.45-4.58 (IH, m).

5.52-5.75 (2H, m), 6.60 (2H,
d), 6.73 (IH, q) 6.89 (2H, d),
7.12 (18,t) 7.27-7.35 (2H
, m) 7.57-7.66 (3H, n+), 7.9
8-8.03(lH,m)IR(KBr)cm-
' :2950.2875.1760.1740145
0, 1420.12g0.1250.10g0.100
0. 910° Example 38 5-yl)biphenyl-4-yl 1methyl]bemidazole-7-carpoxylate Yield 75% Melting point 92-95°C Elemental analysis C (%) H (%) N (%) Calculated value 64.
46; 5.76; 14.55 Actual value: 64.56; 5.
69;14.52'H-NMR (200MH2, CDC
l23) δ: 0-86(3H,t), 1.21
(3H,t), 1.27(,43(2H,m), 1
．． 42 (3H, d), 1.46-1.69 (2H,
m), 2.50 (2H, t), 4.13 (2H, d
q), 5.485.73 (2H, m), 6.56 (
2H, d), 6.72 (lH, q), 6.86 (2
H, d), 7.09 (IH, t), 7.19-7.
23 (IH, m), 7.29-7.34 (LH, m)
, 7.55-7.64 (3H, m), 7.97-8
．． 01 (IH.

m) I R(KB r) Cm-': 1760. 17
30. 1410. 1375°1275, 1245
．． 1070. 990. 760 Example 39 Luboquinlate yield 71% Melting point 123-125'c Elemental analysis value C5tHzsNaOs・l/2H20 as C (%) H (%) N (%) Calculated value: 64.91; 5.10; 14.65 Actual value: 6
4.79; 4.82; 14.34'H-NIJR (20
0MHz, CDCff5) a: 0-84 (3H
,t), 1.221.40(2H,m), 1.53
-1.68 (2H, m), 2.16 (3H, s).

2.46 (2H, t), 4.81 (2H, s), 5
．． 54 (2H, s), 6.53 (2H, d), 6.
86 (2H, d), 7.08-7.22 (2H, m)
, 7.437.38 (IH, m), 7.58-7.
65 (3H, m), 7.95-8.00 (IH.

m) I R(KB r) cm”: 1820.172
0.1400.1300°1275, 1250.122
0.1185.1105.1000. 745 Example 4
0 Lupoxylate ethyl 2-butyl-1-[[2'-(l H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carpoginlate (0,72 g
) was dissolved in ethylene glycol (15d), and sodium hydride (60% oil-based, 0.25%
After adding g), the reaction solution was stirred at room temperature for 15 hours. The reaction solution was poured into ice water (100ml), made acidic by adding formic acid, and the resulting precipitate was extracted with ethyl acetate (100III2). The organic layer was washed with water, dried, and then concentrated to dryness. The residue was recrystallized from acetone to give colorless crystals (0.49 g, 6
6%).

Melting point 145-147℃ Elemental analysis value CxaHzsN*Os・l/2 C, H,
C as O (%) H (%) N (%) Calculated value: 67.41; 5.94; 15.99 Actual value:
67.19; 5.84; 15.79'H-NM
R(200MH2, CDC(23)δ: 0.93(3
H, t), 1.231.97 (4H, m), 2.1
3 (3B, s), 2-87 (2H, t), 3.77
(2H, t), 4.23 (2H, t), 5.73 (
2H,s), 6.77(2H,d).

7.00 (2H, d), 7.20 (IH, t), 7
．． 43-7.93 (6H, m) I R (Nujol)
cm-': 3340 1715. 1410.
12901265, 1035. 755 Example 41 2-Butyl-1,-[[2'-(l H-tetrazol5-yl)biphenyl-4-yl 1methyl-benzimidazole-7-carboxylic acid (0,4 g), 4(2- hydroxyethyl)morpholine (0,15 g) and diethylphosphorocyanidate (0,1 g) in DMF (2 m)
Dissolve triethylamine (0.06 g) in D under water cooling.
MF solution (1-) was added and the mixture was stirred at room temperature for 30 hours. The residue obtained by concentrating the reaction mixture was purified by silica gel column chromatography to give a colorless powder (0
,3g.

65%). The product was dissolved in methanol and IN-
After adding HCI (1,242) and stirring at room temperature for 2 hours, the residue obtained by concentration was diluted with CH2Cl, -)r,o
The aqueous layer was made alkaline with an aqueous solution of Na HCOs, and then extracted with CH and CI.

The CHzCIx solution was mixed, washed with water, dried, and concentrated. The resulting residue was purified by silica gel column chromatography to obtain colorless fine crystals (0.19 g, 87%).

Melting point 98-1106C Elemental analysis value CstHs, N to 3・315Hto
Calculated values as C (%) H (%) N (%):
66.67, 6.33; 17.0
1 Actual value: 66.41; 6.15,
16.89'HNMR (200MHz, CD Cl2
s) a: 0.93 (3H, t).

1.34-1.52 (2H, m), 1.71-1.
88 (21 (, m), 2.58 (4 Hbr t),
2.85 (2H, t), 2.94 (2H, br t
), 3.39 (2H.

br t), 4.10 (2H, br t), 5.6
5 (2H, s), 6.63 (2H.

d), 6.96 (28, d), 7.25 (IH, t
), 7.4O-7-61 (4H, m).

7.77 (IH, dd), 7.83 (ILd) The following compounds (Examples 42-43) were obtained in the same manner as in Example 41.

Example 42 Colorless powder yield 55% Melting point 210-213°C Elemental analysis C33H37N 70 x 315H! ○
Calculated values as C (%) H (%) N (%):
68.99, 6.70; 17.0
7 Actual value: 68.93; 6.59;
16.94' HN M R (200MHz, C
D CQs) δ: 0.96 (3H, t) 1.27-1
．． 58 (8H, m), 1.79-1.94 (2H, m
), 2.72-2.85 (4H, m), 2.93 (
2H, t), 3.20-3.31 (2H, m).

4.10-4.27 (2F1.m), 5.63 (2H
, br s), 6.59-6.70 (2H, m),
7.04 (2H, d), 7.26 (IH, t), 7
．． 36-7.50 (4H, m), 7.72-7.77
(It(, m), 7.98 (IH, dd) Example 43 [[2'-(IH-tetrazol-5-yl)bif Colorless powder Unyield rate 91% Melting point 206-208°C Elemental analysis value C3° Hs s N t Oj・2.IH
, O as C (%) H (%) N (%) Calculated value: 64.18; 6.68;
17.46 Actual value: 64.31; 6.4
0 ; 17.16' HN M R (200MH
z, CD CQs) δ: 0.96 (3) 1. t).

1.39-1.57 (2H, m), 1.79-1.9
4 (2H, m), 2.34 (6H.

s), 2.94 (2H, t), 3.10 (2H, b
r t), 4.19 (2H, brt), 5.66
(2H, s), 6.63 (2H, d), 7.03 (
2H, d).

7.27 (IH, t), 7.39-7.54 (4H,
m), 7.73-7.78 (IFI.

m), 7.97 (IH, da) Example 44 Sylate methyl 1-[(2'-noanobiphenyl-4yl)methyl]-2-methoxymethylbenzimidazole-7-
Carpoxylate (0.4 g) and trimethyltin azide (1.0 g) were dissolved in toluene (10 m) and heated under reflux for 49 hours. The residue obtained by concentrating the reaction solution is
After being dissolved in methanol (6d) and IN-MCI (6t12) and stirred for 3 hours, the resulting residue was concentrated in CH2Cl2-H2O and neutralized with IN-NaOH. The organic layer was washed with water, dried, and concentrated. The resulting residue was purified by silica gel column chromatography to obtain crude crystals, which were recrystallized from ethyl acetate-isopropyl ether to give colorless needle crystals (0.3 g, 68% ) was obtained.

Melting point 191-194°C Elemental analysis value C! SH21N so s・315H,O
Calculated values as C (%) H (%) N (%):
64.53; 5.03; 1g, 0
6 Actual value: 64.57; 4.94;
17.97'HNMR(20ON)Iz, CDC
(2s) a: 3.27 (3H, s).

3.66 (3H, s), 4.21 (2H, s), 5
．． 62 (2Ls), 6.59 (2H, d), 6.8
7 (2H, d), 7.16 (1B, t), 7.30
-7.36(21(,m), 7.55-7.63(3
H, m), 7.93-7.99 (LH, m) Example 4
The following compounds (Examples 45-47) were obtained in the same manner as in Example 4.

Example 45 Colorless powder (75%) 'H-NMR (200 MHz, CDC et al.) δ: 1
．． 12(3H,t)1.23(3)1. t), 2.4
6 (2H, q), 4.11 (28, q), 3.36
(2H,s), 5.63(2H,s), 6.58(
2H, d), 6.87 (2H, d).

7.10-7.36 (3H, m), 7.56-7.6
4 (38, m), 7.97-8.04 (IH, m) Example 47 Silate colorless powder' H-N MR (200 MHz, CD CI23
) δ: 1.14 (3H, t) 1.21 (3B, t),
3.45 (2H, q), 4.20 (2H, q),
4.85 (2H, s), 5.89 (2 days, s),
6.95 (2H, d), 7.10-7.40 (3
Lm), 7.56-7.70 (3H, m), 7.9
6 (1B, dd) Example 46 Xylard colorless powder (56%) 'HNMR (200MHz, CDCQs) J
: 1.21 (3H, t).

2.03 (3H, s), 4.11 (2H, q), 5
．． 63 (2H, s), 6.60 (2H, d), 6.
91 (2H, d), 7.15-7.40 (3H, m)
, 7.557.68 (3H, m), 8.0O-8,1
0(IH,m)Example 48
-Tetrazol-5-yl)biphenyl-4yl]methyl]benzimidazole-7-carpoxylate in the same manner as in Example 44.

Pale yellow powder (80%) 'HNMR (200MHz, CD CQs) δ
: 1.20 (3H, t).

4.17(2H,q), 4.82C2H,br s)
, 5.56(2+(,br s)6.65(2H,d
), 6.86 (2H, d), 6.82-6.95 (
lH, m).

7.21-7.54 (4H, m), 7.62 (LH, d
), 7.75-7.82 (IH, m) Example 49 Methyl 2-methoxymethyl-1-[(2'-(IH-
Tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carpoxylate (0,
2g) in methanol (10III2) and IN-Na
0H (1,5Il12) and heated at 80°C for 20 hours, the residue obtained by concentration was dissolved in water and the crude crystals obtained were acidified with DMF-methanol-H2O.
Recrystallized from to give colorless prismatic crystals (0.16g, 80%)
I got it.

Melting point 272-274'C Elemental analysis value C24HzoN so 3 (MW 440
-46) as C (%) H (%) N (%)
Calculated value: 65.45; 4.58; 1
9.08 Actual value: 65.32; 4.47
; 18.95' H-NMR (200MH
z DMSO-da) δ: 3.28 (3H, s).

4.68(2)r,s), 5.87(2H,s),
6.80 (21 (, d), 6.98 (2H, d),
7.29(l)1. t), 7.45-7.70(5)
1. m), 7.91 (IH, dd) The following compound (Example 5O-54
) was obtained.

Example 50 Colorless powder yield 80% Melting point 243-245°C Elemental analysis C25H2□N, 03・l/2H, ○(M
W 463.50) as C (%) H (%) N (%) Calculated value: 64.78; 5.00;
18.13 Actual value: 64.99; 4.
97; 18.26' H-NMR(200
MHz, DMSO-d, ) δ: 1.01 (3H
,t).

3.48 (2H, q), 4.72 (2H, s), 5
．． 89 (2H, s), 6.81 (2H, d), 6.
99 (2H, d), 7.29 (IH, t), 7.4
4-7.70 (5H, m), 7.91 (lH, dd) Example 51 Colorless powder yield 82% Melting point 270-272°C Elemental analysis value C24H! . N*OxS -1/2HzO
(MW 465.54) C (%) H (%) N (%) Calculated values:
61.92; 4.55; ], 8.05
Actual value: 61.94; 4.44;
18.20' H-N M R(2Of)M)Iz
, DMSO-da) δ 2.09 (3H, s
) 3.98 (2H, s), 5-89 (2H, s),
6.80 (2H, d), 7.00 (2H, d), 7
．． 27(IH,t), 7.45-7.69(5t(,
m), 7.87 (lH, dd) Example 52 Colorless powder yield 65% Melting point 292-2948C Elemental analysis value C23H+aN so h・3/lOH,
○ (MW 431.84) C (%) H (%) N (%) Calculated values:
63.97, 4.34; 19.46 Actual value: 64.01; 4.29; 1
9.49' H-NMR (200MHz, DMS
O-da) δ: 4.72 (2H, s).

5.92(2)1. d), 6.83 (2H, d),
6.98 (2H, d), 7.27 (IH, t), 7
．． 45-7.68 (5H, m), 7.88 (18, dd
) Example 53 Colorless crystal yield 76% Melting point 157-160°C Elemental analysis CzsHxxNaOxS・9/10H20
As C (%, I H (%) N (%) Calculated value: 61.69; 4.93・17.2
6 Actual value: 61.75; 4.91;
17.26' HN M R (200MHz, D
MSO-ds) δ: 1.18(3H,t)2.54(
2H, q), 4.01 (2H, s), 5.89 (2
H,s), 6.80(2H,d), 7.00(2H
, d), 7.27 (IH, t), 7.45-7.6
8 (5H, m), 7.87 (lH, dd) Example 54 Colorless powder yield 48%' HNMR (200MHz, DMSO-da
:) δ: 2.66 (38, s) 4.42 (2H, s)
, 5.84 (2H, s),' 6.79 (2H, d)
, 7.00 (2H, d), 7.27-7.68 (6H
, m), 7.87 (IH, d) The following compounds (Examples 55-58) were obtained in the same manner as in Example 31.

Example 55 Xylard colorless powder Yield 54% Melting point 186-188°C Elemental analysis C25H22N802S・C (%)
H (%) Calculated value: 62.61; 4.83; Actual value: 62.82; 4.63;' HN
MR (200MHz, CD CQ3'11/2
N (%) as H and O 17.52 17.69 δ: 2.03 (3H, s).

3.70 (3H, s), 3.36 (2H, s), 5
．． 63 (28, s), 6-64 (2H, d), 6.
94 (2H, d), 7.18 (1, H, t), 7.
30-7.40 (2H, m), 7.57-7.66 (3
H, m), 8.02-8.07 (IH, m) Example 5
6 Xylard pale yellow powder yield 49% Elemental analysis value C (%) H (%) N (%) calculated value as CzsH24N*02S・l/2H20:
63.27 i 5.11 i 17.0
351! Measured value: 63.42; 4.87
i 16.92'H-NMR (200MHz,
CDC et al.) δ: 1.09 (3H, t).

2.42 (2H, q), 3.22 (2H, s), 3
．． 64 (3H, s), 5.57 (2H, s), 6.
53 (2H, d), 6.84 (2H, d), 7.1
3 (2H, d).

7.31-7.38 (IH, m), 7.56-7.65
(3H, m), 7.89-7.98 (IH, m) Example 57 Methyl 2-hydroquine methyl-1-[2” xylade colorless powder yield 30% 'H-NMR (200MHz, CD CI2.)
δ: 3.63 (3H, s).

4.77C2H,s), 5.75(2H,s), 6
．． 76 (2H, d), 6.99 (2H, d), 7.
23(II(,t), 7.39-7.62(5)1.
m), 7-90 (IH, dd) Example 58 Silate colorless needle crystal yield 61% Melting point 214-217'C Elemental analysis value C2@H24N a Os・115H2
C (%) H (%) N (%) Calculated value as 0: 66.08, 5.18;
17.87 Actual value: 66.15; 5.2
1; 17.80' H-NMR (200M
Hz, CD CQ3) δ: 1.14 (3H
, t) 3.44 (2H, q), 3.68 (3H, s)
, 4.13 (2H, s), 5.63 (2H, s),
6.61 (28, d), 6.89 (2H, d),
7.16 (IH4).

7.19-I39 (2H, m), 7.57-7.64
(3B, m), 7.97-LO2(In, m) Example 59 Lardethyl 2-hydroxymethyl-1-[[2'-(IH
-tetrazol-5-yl)biphenyl-4-yl1methyl]benzimidazole-7-carpoxylate (0
, 2g) in CH,CI□(3-), thionyl chloride (0.3m) was added dropwise and the mixture was heated under reflux for 3 hours. The reaction solution was poured into ice water, and the organic layer was washed with water, dried, and concentrated to give a pale yellow amorphous product (0.2 g, 96%).
I got it.

'H-NMR (2001JHz, CD CN5
) 8: 1.29 (3H, t).

4.19 (2B, q), 4.63 (21 (, s),
5.77 (2H, s), 6.75 (2H, d)
, 7.03 (2H, d), 7.28 (IH, t),
7.35-7.39 (IH, m), 7.56-7.
72 (4H, m), 8.06-8.11 (IH, m'
) Example 60 Ethyl boxylate 2-chloromethyl-1-r[2'-(lHtetrazol-5-yl)biphenyl-4-yl 1-methyl]
Benzimidazole-7-carpoquinlate (0.2g
) in acetonitrile (5-), 40% methylamine in methanol (0.33 g) was added and the mixture was heated at 606 C for 77 hours. The reaction solution was cooled to obtain pale yellow prism crystals (0.12 g, 61%).

Melting point 248-250°C' HNMR (200MHz, DMSO-da)
δ: 1.14 (3H, t) 2.62 (3H, s),
4.16(2)1. q) 4.39 (2H, s),
5.71 (2H, s), 6.73 (2H, d), 7
．． 03(21(,d), 7.27-7.46(4H,
m), 7.54-7.63 (2H, m), 7.94
(IH, dd) The following compound (Example 6162) was obtained in the same manner as in Example 1.

Example 61 - Colorless prism crystal yield 71% 'HNMR (90MHz, CD CQ3) δ:
0.87 (6H, d).

1.13 (3H, t), 1.23 (IH, t), 1
．． 87-2.40 (IH, m) 2.00 (IH, s),
2.27 (2H, d), 4.03 (2H, q),
4.13 (IH, q), 5.47 (2H, s), 6
．． 43 (2H, d), 6.73 (2H, d).

6.87-7.70 (6)1. m), 7.90-8.
00 (IH, m) Example 62 Methyl]benzimidazole-7-carpoxylate colorless prismatic crystals Yield 43% Melting point 128-1306C'HNMR (9f) MHz, CDCL) δ: 0.87
(3H,t)1.0O-117(6H,m), 1.2
3 (IH, t), 1.50-1.90 (2Hm),
2.03 (LH, s), 2-63-3.03 (lH,
m), 4.0O(2H,q).

4.13 (IFI, q), 5.57 (IH, d),
5.77 (IH, d), 6.50 (2H, d), 6
．． 77 (LH, m) I R (Nu j o l) cm-
': 2720.1730.1450°1280, 12
65.1200. 760. 765 The following compound (!!!Example 63-64) was obtained in the same manner as in Example 49.

Example 63 Colorless powder yield 62% Melting point 205-207°C (decomposition) Elemental analysis values C (%) H (%) N (%) calculated values as C26H24N802/215H20:
67.93; 5.44, 18.23 Actual value: 67.98; 5.63; 1
8.43' HN M R (9011Hz, CD
CI23) δ: 1.57 (6H, d).

3.40-3.83 (LH, m), 6.00 (2H,
s), 6.90 (2H, d).

7.13 (2H, d), 7.43-7.83 (5H,
m), 7.97-8.12 (2H, m)I R(Nu
j o l) cm-': 2460.1690.14
10°1290, 1245. 1200. 1120
．． 760 Example 64' HNMR (90MHz, DMSO-di)
δ: 0.83 (3H, t) 1.17 (IH, t)
, 1.53-2.13 (2H, m), 2.73-3
．． 13 (LH, m), 3.63 (E, q), 5.9
0 (2H, s), 6.80 (2H, d).

7.03 (2H, d), 7.23 (IH, t), 7
．． 33-7.97 (78, m) I R (Nu j o
l) cm-': 2600.1700.1450°14
10, 1275.1230.1200.1140. 7
50 The following compound (Example 656) was prepared in the same manner as in Example 19.
6) Get it.

Example 65 Colorless prism crystal yield 79% Melting point 184-186°C Elemental analysis Cx*H24N *Ox ” l/2Et
Calculated values for C (%) H (%) N (%) as OH: 68.20; 5.72; 1
7°67 Actual value: 67.96; 5.71
; 17.46 Pale yellow powder uncollected rate 35% 'HNMR (200MHz, CDCQs) δ: 2.
60 (2H, t).

3.61 (2H, t), 3.19 (3H, t), 3
．． 63 (3H, t), 5.60 (2H, s), 6.
56 (28, d), 6.85 (2H, d), 7.0
7-7.12 (2H, m), 7.30-7.35 (L
H, m), 7.51-7.65 (3Lm) 7.96 (
IH, cld) Example 66 Pale yellow powder yield 16%' HN MR (200 MHz, CD Cf2s)
δ: 2.09 (3H, t) 3.63 (3H, s),
2.72-2.96 (4H, m), 5.65 (2H,
s).

6.60 (2H, d), 6.87 (2H, d), 7
．． 06-7.20 (2H, m).

7.29-7.34 (IH, m), 7.54-7.6
3(3H,m), 7.99-8.05(LH,m) Example 67 2-Butyl-1-[[2'=(I H-tetrazole 5
-yl)piphenyl-4-yl1methyl]benzimidazole-7-carboxylic acid (2,0 g)NaHCOx (1
, 1g) and methyl iodide (1°5g) in DMF (1g) and methyl iodide (1°5g).
0ml) and stirred at room temperature for 15 hours. The reaction solution was diluted with water and extracted with ethyl acetate. The organic layer was washed with water, dried, and concentrated, and the resulting residue was purified by silica gel column chromatography to obtain the 1-methyl compound (0,95
g.

45%) and 2-methyl compound (0.36g, 17%) were obtained.

l-Methyl compound (67a): Melting point 200-201'C Elemental analysis value C (%) as C25HzsNsOz
H (%) N (%) Calculated value: 69.98
; 5.87 ; 17.49 Actual value:
69.67; 5.80; 17.36'
HNMR (200MHz, CD CQs) δ:
0.97 (3H, t).

1.39-1.58 (2H, m), 1.81-1.9
7 (2B, m), 2.91 (2Ht), 3.16 (
3)1. s), 3.74 (3H, s), 5.72 (
2H,s).

6.77 (2H, d), 7.00 (2H, d), 7
．． 25 (IH, t), 7.487.69 (5H, m)
, 7.95 (LH, dd) 2-methyl compound (67b): Pale yellow protein HNMR (200MHz, CD CQs) δ
: 0.96 (3H, t).

1.38-1.57 (2H, m), 1.8O-1-9
6 (2H, m), 2.92 (2H.

t), 3.71 (3H, s), 4.18 (3) 1.
s), 5.73 (2H, s) 6.77 (2) 1. d)
, 7.06 (2H, d), 7.24 (IH, t),
7.357.55 (3H, m), 7.59 (IH,
dd), 7.80 (LH, dd), 7.94 (IH
, dd) IR (Ne at) cm”: 1725.1520.
1460°1435, 1400.1360.1280.
1265.1220°1200, 1125. 760 Example 68 Ethoxycarbonylaminobenzimidazole 2-butyl-1-[[2'-(I H-tetrazol 5-yl)
piphenyl-4-yl1methyl]benzimidazole-
7-carboxylic acid (0,94 g).

Diphenylphosphoryl azide (0.61 g) and triethylamine (0.61 g) were dissolved in DMF (6 ml) and stirred at room temperature for 7 hours. The crude crystals obtained by concentrating the reaction solution were purified by silica gel column chromatography to obtain colorless crystals (68a and 68b).

Formylamino compound (68a): Colorless crystals (0.26g, 29%) Melting point 290-292°C (decomposition) Elemental analysis value C (%) as Cx5HzsNyO
H (%) N (%) Calculated value: 69.16;
5.58; 21.71 Actual value: 6
9.29; 5.51 i 21. ．． 94'
H-NMR (200MHz, CD CI23)
δ: 0.84 (3H, t).

1.22-1.40 (2H, m), 1.5Er1.7
1 (21 (, m), 2.70 (2Ht), 5.55
(2H, s), 6.79 (IH, d), 6.89 (
2H, d).

6.98-7.07 (31 (, m), 7.43 (2H
, d), 7.51-7.70 (38, m), 8.2
7(18,s)I R(KB r) cm-': 3
340. 1630.1530°1510, 1420
．． 1400. 750. 730-ester carbonylamino compound (68b): Colorless crystals (0.31g, 31%) Melting point 190-194'c (decomposition) Elemental analysis value CzaHzsN 702.0. C (%) H (%) N (%) Calculated values as IH, 0:
67.62; 5.92 i 19.7
1 Actual value: 67.43; 5.81;
19.70'H-NMR (200MHz, CDC
et al.) δ: 0.87 (3H, t).

1.18(31(,t), 1.25-1.39(3H
, m), 1.56-1.71 (2H.

m), 2.50 (2H, t), 3.99 (2H, q
), 5.37 (2H, s).

6.07 (IH, s), 6.66 (2H, d), 6-
90-7.05 (5H, m).

7.34 (IH, dd), 7.55-7.64 (2H
, m), 800 (IH, dd) I R (Ne a t
) cm-' : 1700.1520.1250° Example 69 2-butyl-1-r[2'-(l H-tetrazole 5
-yl)biphenyl-4-yl]methyl]-7(dimethylaminemethyl)benzimidazole Synthesized in the same manner as in Example 44.

Colorless crystals (56%) Melting point 178-180'c (decomposition) Elemental analysis value C21H31N?・2HC1・2H20-1
C (%) H (%) N as /2AcOEt
(%) Calculated value: 58.25; 6.68;
15.85 Actual value: 58.42; 6.
42; 15.61' H-NMR(200
MHz, DMSO-d,)δ: 0.91(3H,t
).

1.33-1.51 (28, m), 1.71-1.8
6 (2H, m), 2.50 (6H.

s), 3.17 (2H, t), 4.32 (28, s
), 5.92 (2H, s).

7.07 (2H, d), 7.14 (2t (, d),
7.49-7.72 (5H, m).

7.80 (IH, d), 7.92 (IH, d) I R
(KB r ) cm”: 3400.1500.
1470°1435, 1420. 750 The following compounds (Examples 70-71) were prepared in the same manner as in Example 44.
) was obtained.

Example 70 Benzimidazole-7-carboxylic acid colorless prismatic crystals (78%) Melting point 213-214°C Elemental analysis value C27H□N a C (%) H (%) N (%) calculated value as Ox・l/2H20 :
68.19; 5.72; 17.6
7 Actual value: 68.52: 5.55,
17.62' HNMR (200MHz, CD
CQs) δ: 0.95 (3H, t) 1.38-1.
57 (2H, m), 1.80-1.95 (2H, m)
, 2.99 (2H.

t), 3.18 (3H, s), 5.82 (2H, s
), 6.80 (2H, d).

6.97 (2H, d), 7.27 (IH, t), 7
．． 48-7.68 (4H, m) 7.80 (IH, d),
7.98 (1B, d) I R (KB r) cm-
': 1700.1520.1470.1445°1
435 1410, 1290.1280.1230.1
185.1145°1120, 1100. 820.
770. 760. 745. 730 Example 71 Melting point 226-228°C (decomposition) Elemental analysis value C2AH2sl'J, o2・0.7H
C (%) H (%) N (%) Calculated value as 20: 67.68; 5.76; 1
7.54 Actual value: 67.48; 5.51
; 17.26'HNMR (2001JHz,
CDCQs) δ: 0.94 (3H, t) 1.38
-1.56(21(,m), 1.79-1.94(2
H, m), 3.07 (2Ht), 4.22 (3H,
s), 5.84 (2H, s), 6.81 (2H, d
) 7.06 (2H, d), 7.25-7.55 (4H
, m), 7.74 (IH, d).

7.81 (lH, ad), 8.00 (lH, d) I
R(KB r) cm-': 1700.1510
．． 1450°1430, 1410.1360.1290
．． 1240.1190°1150, 1120.1100
．． 1060.1035.1000°820, 760.
750. 740. 720 Example 72 Colorless prismatic crystals (71%) 2-butylponate-1-[[2'-(l H-tetrazole 5
-yl)biphenyl-4-yl 1 methyl]benzimidazole-7-carboxylic acid (0,71 g).

K, CO, (0.21 g) and methyl iodide pivalate (0.36 g) were dissolved in DMF (2 ml) and stirred at room temperature for 17 hours. The reaction solution was digested with water and 1N-H
The mixture was made acidic (pH 3-4) with Cl and extracted with ethyl acetate. The organic layer was washed with water, dried, and concentrated, and the resulting residue was purified by silica gel column chromatography to obtain a colorless powder (0.2 g, 23%).

Melting point 188-191'C (decomposition) Elemental analysis value C1H34N604・0.6H,C as O (%) H (%) N (%) Calculated value: 66.56; 6.14;
14.55 Actual value: 66.82; 6.2
8; 14.13' HN M R (200MH
z, CD CQs) δ: 0.94 (3H, t).

0.96 and 1.18 (9H, s), 1.36-1.
55 (2H, m), 1.77-1.93 (2H, m
), 2.90-2.97 (2H, m), 5.39 (
1,5H,s).

5.81 (2H, s), 6.36 (0.5H, s),
6.76-6.83 (2H, m).

6.96-7.03 (2H, m), 7.20-7.2
9 (lH, m).

7.38-7.97 (6H, m) I R (KB r) cm': 1760.1
600.1460°1410, 1275.1240.1
125.1100. 760 The following compounds (Examples 73-76) were obtained in the same manner as in Example 36.

Example 73 Pivaloyloxymethyl 2-ethyl-1-[[Example 74 Example 75 Rag-ru-5-yl)biphenyl-4-yl 1-methyl]
Benzimidazole-7-carponquinlate Example 76 Experimental Example 1 Inhibitory effect on angiotensin-■ binding to angiotensin receptor [Experimental method] Doug Las et al.'s method [Endocrinolog
y, ±02°685-696 (1978)] was modified to conduct an angiotensin I [(A-n)-receptor binding inhibition experiment. A-I receptor membrane fraction was prepared from the cortex of bovine adrenal glands.

Compound of the present invention (10-'M or 10'''By1)
IXl, 85 kBq/50 μl) was added to the receptor membrane fraction and incubated for 1 hour at room temperature. Bound and free 12J A II were filtered (Whatm
The radioactivity of 7=+261-A-I [7=+261-A-I] bound to the receptor was measured.

[Experimental result] Experimental results regarding the compounds of the present invention are shown in Table 1.

Experimental Example 2 A-I [Suppressive effect of the compound of the present invention on pressor response action [Experimental method] Jcl: SD rats (9 weeks old, male) were used. On the day before the experiment, an indwelling cannula was placed in the femoral artery and vein under Bendoparbital Na anesthesia, and the animals were kept without food and with free access to water until just before the experiment. In experiment 5, the arterial cannula was connected to a blood pressure transducer and mean blood pressure was recorded polygraph. Before drug administration, control A-II (l
The pressor response due to intravenous administration of OOng/kg) was determined. The drug is administered orally, and then A-n at each measurement point.
was administered intravenously, the pressor response was similarly determined, and the response before and after drug administration was compared to determine the inhibition rate.

[Experimental result] Experimental results regarding the compounds of the present invention are shown in Table 1.

Claims (1)

[Claims] Formula ▲ Numerical formula, chemical formula, table, etc. ▼ [In the formula, R^1 represents an optionally substituted alkyl group, and R^2 and R^3 each form an anion. Ring A represents a benzene ring which may further have a substituent in addition to the group represented by the formula R^2, and X represents a group in which a phenylene group and a phenyl group are directly or in an atomic chain. A compound or a salt thereof, which indicates that the compound is bonded through two or less spacers.